A Modular Four-Component Route to Substituted 1,7,9-Decatrien-3-ones Using a Chloro-Substituted Phosphorane as Key C₃ Building Block

Abstract

An efficient and flexible four-component route to substituted 1,7,9-decatrien-3-ones was established by alkylation of sodium dialkyl malonates with a chloro-substituted phosphorane followed by a Wittig reaction with the corresponding carbonyl compound. The resulting enones were alkylated at their malonate unit with sorbyl bromide to give the title compounds in good overall yields. In an attempt to improve the overall yield by using in situ generated sorbyl tosylate we discovered the formation of an unusual bicyclic product with a 3-oxocyclopenta[b]furan core that is formally generated by an oxidative dimerization of the employed precursor enone. The structure of this compound was unambiguously determined by an X-ray crystal analysis.

Intramolecular Diels–Alder reactions allow direct and often stereoselective approaches to bicyclic compounds of high importance.[1] In many examples, bicyclo[4.3.0]nonane, bicyclo[4.4.0]decane or bicyclo[5.4.0]undecane systems were smoothly available either by thermal- or (Lewis) acid-promoted cycloadditions.[2] However, the preparation of the cycloaddition precursors is frequently not trivial and multi-step syntheses are often required to construct the corresponding triene systems. In earlier studies,[3] we demonstrated that donor-acceptor cyclopropane-derived 1,7,9-decatrien-3-ones are excellent precursors for these intramolecular Diels–Alder reactions and applied this approach to the diastereoselective synthesis of natural products such as α-eudesmol[3e] or to drug precursors such as dihydromevinolin.[3f] In continuation of these investigations, we were looking for enantioselective versions of the cycloaddition and we were therefore searching for suitable prochiral starting materials that allow a generation of the stereogenic centers during the Diels–Alder step under the influence of an enantiopure promoter or catalyst. Prochiral 1,7,9-decatrien-3-ones of type B were identified as suitable precursors for bicyclo[4.4.0]decene derivatives A (Scheme [1]), but the approach to these compounds via siloxycyclopropane carboxylates[4] failed due to the instability of this kind of small ring compounds activated by two alkoxycarbonyl groups.

Therefore, an alternative and flexible route to B by combination of the 1,3-dienyl moiety C and the functionalized enone D was envisioned. The required enones D should either be prepared by a Wittig–Horner reaction of carbonyl compounds E with the functionalized phosphonate H or by a standard Wittig reaction of aldehydes or ketones E with the functionalized phosphorane F and dialkyl malonate G as precursors. This second approach turned out to be quite efficient and we describe here the details of the four-component approach to a series of 1,7,9-decatrien-3-ones B in detail. The crucial phosphorane F serves as the central 1,3-zwitterionic synthon in this route to the desired products B.

Easily available 1-chloro-3-(triphenyl-λ⁵-phosphanylidene)propan-2-one (1)[5] was first combined with the sodium salt of the corresponding dialkyl malonate in the presence of sodium iodide to generate a chain-elongated phosphorane (Scheme [2]). A mixture of DMF and THF was most suitable to fully dissolve the components. Addition of sodium iodide was required to increase the reactivity of the alkylating agent 1 by an in situ Finkelstein reaction to generate the corresponding alkyl iodide. After stirring for 5 days at room temperature, the formed C-alkylated malonate was not purified, but the crude product was directly treated with a solution of the corresponding aldehyde or ketone (1.1 to 10 equiv) after an exchange of the solvent. The expected Wittig reactions afforded the required enones 2–8 in good overall yield and with high E-selectivity (Table [1]). This three-component reaction worked very well with dimethyl malonate or di(tert-butyl) malonate – the latter being the preferred precursor due to the higher stability of products in subsequent reactions. Reactive aliphatic aldehydes such as acetaldehyde (Table [1], entries 1 and 3), functionalized aldehydes (entries 2 and 5), aromatic or heteroaromatic aldehydes (entries 4 and 6), and a reactive ketone like ethyl pyruvate (entry 7) were successfully used in this reaction sequence that allows the preparation of a small library of functionalized enones. Only with the ethyl glyoxylate and the siloxy-substituted acetaldehyde (entries 2 and 5) the overall yield was lower than 65%. In the crude products the E:Z ratios are in the order of 90:10 or even higher. By column chromatography pure or highly enriched E-isomers could be isolated in most cases (entries 1, 3–7).

As an alternative method to the three-component reaction, we also examined the synthesis of enone 4 via the above mentioned Wittig–Horner approach. We used the brominated unsaturated phosphonate 9 that has been introduced by Piers et al.[6] as a useful C₃ building block and alkylated the sodium malonate with this electrophile (Scheme [3]). The expected product 10 was smoothly formed in 95% yield and its enol ether unit was subsequently hydrolyzed with dilute hydrochloric acid to provide the desired substituted phosphonate 11. For the Wittig–Horner reaction of this intermediate with acetaldehyde we examined several conditions. The use of Hünig base in the presence of lithium chloride[7] in acetonitrile afforded the highest yield in this step furnishing enone 4 in 62% yield and with excellent E-selectivity. The reaction sequence depicted in Scheme [3] demonstrates that this pathway allows the preparation of the required enones, however, it did not offer clear advantages over the three-component reaction of Scheme [2].

In the final step of our four-component approach to the desired 1,7,9-decatrien-3-ones B, the introduction of the 1,3-dienyl substituent has to be achieved. The enones 2–8 were deprotonated again with sodium hydride in a DMF/THF mixture and the generated malonate anion was then treated with 1-bromo-2,4-hexadiene (12) (sorbyl bromide) (Scheme [4]). The expected alkylation products 13–18 were obtained in yields between 41–77% (Table [2]). Only enone 3 bearing a C=C bond with two adjacent electron-withdrawing groups did not provide any alkylation product (Table [2], entry 2). We assume that the high reactivity of this electrophilic unit causes competing (poly)condensation reactions leading to unidentified oligomers and thus preventing the desired reaction. The malonate anions generated in the other entries are apparently sufficiently stable to survive and to undergo the reaction with the external electrophile 12. A conceivable 5-endo-trig cyclization of these malonate intermediates to form cyclopentanone enolates did not occur, at least products generated by this process were not observed. This ring closure is unfavorable according to the Baldwin rules.[8]

The moderate (and in part low) yields in the alkylation reaction with sorbyl bromide (12) are certainly caused by the instability and inhomogeneity of this electrophile. The standard method to prepare this reactive compound is the bromination of (2E,4E)-2,4-hexadien-1-ol with phosphorous tribromide, that produces not only the desired E,E-configured compound 12 but also its stereoisomers and the regioisomeric (1E,3E)-5-bromo-1,3-hexadiene in varying amounts (ca. 20–30%).[9] Due to the moderate stability and high reactivity of 12 these by-products cannot be removed by chromatography or other separation techniques. The products derived from the electrophilic side-products were not isolated in course of the alkylation of 2–8 and the yield for 13–18 compiled in Table [2] are those of the pure E,E-configured compounds.

The successful method for the synthesis of 1,7,9-decatrien-3-ones 13–18 was analogously applied to the preparation of the furan-2-yl-substituted compound 20 (Scheme [5]) that is also a good candidate for intramolecular Diels–Alder reactions. Enone 4 was alkylated with the easily available bromide 19 [10] in 58% yield.

In an attempt to improve the overall efficacy of the synthesis of compounds such as 13 we inverted the sequence of reactions employing the literature known compound 21.[11] Its deprotonation with sodium hydride, subsequent reaction with phosphorane 1, and as final step the Wittig reaction with acetaldehyde (Scheme [6]) gave 1,7,9-decatrien-3-one derivative 13 in only 23% overall yield. Hence this sequence seems not to offer advantages. We also tried to prepare compound 21 by palladium-catalyzed reaction[11] of sodium dimethyl malonate and (E,E)-1-acetoxy-2,4-hexadiene,[12] which did not only provide the desired product 21 but also in equal amounts the corresponding regioisomer with the malonate unit at the central position.

As alternative to the problematic sorbyl bromide (12) for the alkylation of enones such as 4 we examined the use of the corresponding sorbyl tosylate 22 (Scheme [7]). For this attempt, (2E,4E)-2,4-hexadien-1-ol was deprotonated at –78 °C with n-butyllithium in THF and subsequently treated with tosyl chloride.[13] The solution containing 22 was then added at –78 °C via a cooled cannula to the sodium malonate generated from 4 and the resulting mixture was stirred at 0 °C. The expected compound 14 was formed; however, in a series of experiments under different conditions, the yield scattered between 17–49%. The desired product was always accompanied by an unknown side-product formed in 6–42%. Gratifyingly, suitable crystals for an X-ray crystal structure analysis could be gained, which showed that this compound has the unique constitution 23 with a 3-oxocyclopenta[b]furan core (Figure [1]) being formed by a combination of two enone 4 moieties. The result of Scheme [7] demonstrates that the use of sorbyl tosylate (22) is not a viable alternative to sorbyl bromide since the side-product formation could not be suppressed under various conditions.

Compound 23 involves an ‘oxidative dimerization’ of enone 4 and a speculative mechanism for this process is presented in Scheme [8]. The suggested scenario requires the formation of the intermediate 25 with a double bond between the carbonyl group and the two alkoxycarbonyl substituents. This intermediate may be formed by tosylation or chlorination of deprotonated 4 to give 24. Base-induced elimination furnishes 25 that undergoes an intramolecular Michael addition with a second equivalent of deprotonated 4 generating intermediate 26. The resulting enolate moiety of 26 then adds intramolecularly to the carbonyl group to form the cyclopentane ring of 27. The alkoxide unit finally closes the second ring to give the furan-3-one unit of 28 that is protonated to the isolated compound 23. Only one diastereomer was isolated, however, we cannot exclude the formation of stereoisomers or other side-products. We assume that the formation of 23 is under steric control placing the substituents around the bicyclic core in the positions with minimal repulsions. The cyclization steps (26 → 27 and 27 → 28) may be under thermodynamic control. This plausible mechanistic scenario is certainly not without alternatives.[15] Of course, the question arises why intermediate 24 can be formed in this sequence, which must be due to unconsumed tosyl chloride in the reaction supposed to generate the sorbyl tosylate (22). Apparently, the O-tosylation of the lithium alkoxide generated was incomplete at –78 °C. The scattering yields under various conditions support this hypothesis. A control experiment subjecting the anion of enone 4 purposefully to tosyl chloride provided 23 in 21% yield. Future studies may demonstrate the generality and scope of this unique reaction pathway to functionalized 3-oxocyclopenta[b]furans.

In this report, we demonstrate that 1,7,9-decatrien-3-ones 13–18 are easily available by using a new and flexible four-component approach with phosphorane 1 as synthetic equivalent of a 1,3-zwitterionic synthon.[16] This key C₃ building block allowed the efficient connection with a nucleophile (malonate anion) and an electrophile (carbonyl compound) leading to enones 2–8 that could be further alkylated with sorbyl bromide (12) to give the title compounds. An alternative method using the Wittig–Horner reagent 11 was also tested, but it did not offer advantages. The use of in situ generated sorbyl tosylate 22 instead of sorbyl bromide resulted in the surprising formation of the bicyclic compound 23 with a 3-oxocyclopenta[b]furan core as side-product. After its structural elucidation, a plausible mechanism is suggested. The stereoselective Diels–Alder reaction of the 1,7,9-decatrien-3-ones will be reported in subsequent publications.[17]

Reactions were generally performed under argon in flame-dried flasks. Solvents and reagents were added by syringes. Solvents were dried using standard procedures (abbreviations in the following text: EA = EtOAc, Hex = hexanes). Reagents were purchased and were used as received without further purification, unless otherwise stated. The starting materials 1,[5] 9,[6] 12,[9] 19,[10] and 21 [11] were prepared according to literature procedures; compound 12 should be stored in the fridge and filtered through a short pad of alumina before use. Reactions were monitored by thin-layer chromatography (TLC). Products were purified by column chromatography on silica gel (32–63 μm). Unless otherwise stated, yields refer to chromatographically homogeneous and spectroscopically pure materials (¹H NMR spectroscopy). NMR spectra were recorded with Bruker (AC 200, AC 300) and JEOL (ECX 400, Eclipse 500) instruments. Chemical shifts are reported relative to TMS (¹H: δ = 0.00) and CDCl₃ (¹³C: δ = 77.0). Integrals are in accordance with assignments; coupling constants are given in Hz. ¹³C NMR spectra are ¹H-decoupled. Standard abbreviations were used to indicate multiplicities. HRMS analyses were performed with a Varian Ionspec QFT-7 instrument (ESI-FT ICRMS). IR spectra were measured with a spectrometer Nicolet 205 FT-IR. Elemental analyses were carried out with a Vario EL Elemental Analyzer. Melting points were measured with a MPD 350 or a Reichert apparatus (Thermovar) and are uncorrected.

Synthesis of Enones 2–8 by Alkylation of Dialkyl Malonates with Phosphorane 1 and Subsequent Wittig Reaction with Carbonyl Compounds; General Procedure 1 (GP 1)

To a suspension of NaH (1.2 equiv, mineral oil was removed by washing with Hex) in a mixture of DMF and THF (5:1) were slowly added at 0 °C the corresponding dialkyl malonate (1.5–2.0 equiv). After stirring for 1 h at r.t., the mixture was cooled to 0 °C and phosphorane 1 (1.0 equiv) was added followed by addition of NaI (1.0 equiv). After stirring for 5 d at r.t., the solvents were removed in vacuo and the residue was dissolved in CH₂Cl₂ und quenched with H₂O. The aqueous phase was extracted with CH₂Cl₂ (3 ×) and the combined organic phases were dried (MgSO₄). The remaining crude product was dissolved again in CH₂Cl₂ and an excess (1.1–10 equiv) of the corresponding carbonyl compound was added. After stirring for 16 h at r.t., the resulting mixture was worked up and purified as described in the individual experiments.

Dimethyl 3-Oxo-4-hexene-1,1-dicarboxylate (2)

Following GP 1, phosphorane 1 (6.00 g, 17.0 mmol), dimethyl malonate (3.37 g, 25.5 mmol), NaH (0.612 g, 25.5 mol), and NaI (2.50 g, 17.0 mmol) in DMF/THF (125 mL/25 mL) were used in the alkylation step. For the subsequent Wittig reaction freshly distilled acetaldehyde (7.50 g, 170 mmol) in CH₂Cl₂ (50 mL) was employed. The solvent was removed in vacuo and the residue was washed with Et₂O (3 × 20 mL) to remove triphenylphosphane oxide. The crude product was purified by flash column chromatography (silica gel, Hex/EA 3:1) to provide two fractions (1:0.414 g, E:Z = 58:42; 2: 1.97 g E only). Combined yield of product 2: 2.38 g (66%, E:Z = 92:8) as colorless oil.

IR (film): 3050 (=C–H), 2950–2860 (C–H), 1750 (CO₂Me), 1700 (C=O), 1640 cm^–1 (C=C).

Signals of (E)-2

¹H NMR (CDCl₃, 200 MHz): δ = 1.85 (dd, J = 2, 7 Hz, 3 H, 5-Me), 3.13 (d, J = 7 Hz, 2 H, 2-H), 3.68 (s, 6 H, 2 × CO₂Me), 3.87 (t, J = 7 Hz, 1 H, 1-H), 6.07 (qd, J = 2, 16 Hz, 1 H, 4-H), 6.85 (qd, J = 7, 16 Hz, 1 H, 5-H).

¹³C NMR (CDCl₃, 50.3 MHz): δ = 18.2 (q, 5-Me), 38.5 (t, C-2), 46.4 (d, C-1), 131.0 (d, C-4), 143.8 (d, C-5), 52.6*, 169.2* (q, s, 2 × CO₂Me), 195.9 (s, C=O); * signals with higher intensity.

Signals of (Z)-2

¹H NMR (CDCl₃, 200 MHz): δ = 2.05 (d, J = 5.5 Hz, 3 H, 5-Me), 3.07 (d, J = 7 Hz, 2 H, 2-H), 3.70 (s, 6 H, 2 × CO₂Me), 3.88 (t, J = 7 Hz, 1 H, 1-H), 6.09–6.31* (m, 2 H, 4-H, 5-H); * signal overlaps with those of (E)-2.

¹³C NMR (CDCl₃, 50.3 MHz): δ = 15.8 (q, 5-Me), 42.5 (t, C-2), 46.5 (d, C-1), 126.5 (d, C-4), 144.3 (d, C-5), 52.5*, 169.4* (q, s, 2 × CO₂Me), 197.1 (s, C=O); * signals with higher intensity.

Anal. Calcd for C₁₀H₁₄O₅ (214.2): C, 56.07; H, 6.59. Found: C, 56.26; H, 6.91.

Dimethyl 5-Ethoxycarbonyl-3-oxo-4-pentene-1,1-dicarboxylate (3)

Following GP 1, phosphorane 1 (0.353 g, 1.00 mmol), dimethyl malonate (0.264 g, 2.00 mmol), NaH (0.048 g, 2.00 mmol), and NaI (0.165 g, 1.11 mmol) in DMF/THF (17 mL/3 mL) were used in the alkylation step. For the subsequent Wittig reaction a 50% solution of ethyl glyoxylate in toluene (0.503 g, 2.46 mmol) was employed. The solvent was removed in vacuo and the residue was dissolved in CH₂Cl_2­ (20 mL) and H₂O was added. The aqueous phase was extracted with CH₂Cl₂ (3 × 20 mL) and the combined organic phases were washed with H₂O (100 mL) and dried (Na₂SO₄). After filtration, the solvents were removed in vacuo and the crude product (0.494 g) was purified by column chromatography (silica gel, Hex/EA 3:1) to afford product 3 (0.139 g, 51%, E:Z = 92:8) as a colorless oil.

IR (film): 2960 (C–H), 1750 (COMe, CO₂Et), 1700 (C=O), 1640 cm^–1 (C=C).

Signals of (E)-3

¹H NMR (CDCl₃, 500 MHz): δ = 1.33 (t, J = 7 Hz, 3 H, CH ₃CH₂O), 3.29 (d, J = 7 Hz, 2 H, 2-H), 3.77 (s, 6 H, 2 × CO₂Me), 3.97 (t, J = 7 Hz, 1 H, 1-H), 4.28 (q, J = 7 Hz, 2 H, CH₃CH ₂O), 6.74, 7.97 (2 d, J = 16 Hz, 1 H each, 4-H, 5-H).

¹³C NMR (CDCl₃, 125.8 MHz): δ = 39.9 (t, C-2), 46.3 (d, C-1), 131.9 (d, C-4), 138.3 (d, C-5), 14.1, 61.4, 165.1 (q, t, s, CO₂Et), 52.9*, 168.8* (q, s, 2 × CO₂Me), 195.9 (s, C=O); * signals with higher intensity.

Signals assigned to (Z)-3

¹H NMR (CDCl₃, 500 MHz): δ = 1.29 (t, J = 7 Hz, 3 H, CH ₃CH₂O), 4.21 (q, J = 7 Hz, 2 H, CH₃CH ₂O), 6.07 (d, J = 12 Hz, 1 H, 4-H), 6.51 (d, J = 12 Hz, 1 H, 5-H).

¹³C NMR (CDCl₃, 125.8 MHz): δ = 125.5 (d, C-4), 140.6 (d, C-5).

Anal. Calcd for C₁₂H₁₆O₇ (272.3): C, 52.93; H, 5.92. Found: C, 51.72; H, 5.18.

Di(tert-butyl) 3-Oxo-4-hexene-1,1-dicarboxylate (4)

Following GP 1, phosphorane 1 (8.16 g, 23.1 mmol), di(tert-butyl) malonate (10.0 g, 46.2 mmol), NaH (1.11 g, 46.2 mmol), and NaI (6.93 g, 46.2 mmol) in DMF/THF (125 mL/25 mL) were used in the alkylation step (6 d). For the subsequent Wittig reaction freshly distilled acetaldehyde (10.3 g, 231 mmol) in CH₂Cl₂ (50 mL) was employed. The solvent was removed in vacuo and the residue was dissolved in CH₂Cl_2­ (20 mL) and H₂O was added. The aqueous phase was extracted with Hex (3 × 20 mL) and the combined organic phases were washed with H₂O (100 mL) and dried (Na₂SO₄). After filtration, the solvents were removed in vacuo and the crude product (17.7 g) was purified by flash column chromatography (silica gel, Hex/EA 8:1, then 4:1) to provide the product 4 (5.41 g, 78%, E:Z = 97:3) as a colorless oil.

IR (film): 3000 (=C–H), 2980–2930 (C–H), 1740 (CO₂ t-Bu), 1700 (C=O), 1640 cm^–1 (C=C).

Signals assigned to (E)-4

¹H NMR (CDCl₃, 300 MHz): δ = 1.46 (s, 18 H, 2 × CO₂ t-Bu), 1.91 (dd, J = 2, 7 Hz, 3 H, 6-H), 3.07 (d, J = 7 Hz, 2 H, 2-H), 3.74 (t, J = 7.2 Hz, 1 H, 1-H), 6.14 (qd, J = 2, 16 Hz, 1 H, 4-H), 6.91 (qd, J = 7, 16 Hz, 1 H, 5-H).

¹³C NMR (CDCl₃, 75.5 MHz): δ = 18.3 (q, C-6), 38.5 (t, C-2), 48.9 (d, C-1), 131.5 (d, C-4), 143.5 (d, C-5), 27.9,* 81.7,* 168.4* (q, 2 s, CO₂ t-Bu), 196.6 (s, C=O); * signals with higher intensity.

Signals assigned to (Z)-4

¹H NMR (CDCl₃, 300 MHz): δ = 1.46 (s, 18 H, 2 × CO₂ t-Bu), 2.10 (d, J = 6 Hz, 2 H, 3 H, 6-H), 2.99 (d, J = 7 Hz, 2 H, 2-H), 3.72 (t, J = 7 Hz, 1 H, 1-H), 6.16–6.19 (m, 2 H, 4-H, 5-H).

¹³C NMR (CDCl₃, 75.5 MHz): δ = 15.9 (q, C-6), 42.6 (t, C-2), 49.0 (d, C-1), 127.1 (d, C-4), 143.5 (d, C-5), 27.8,* 81.6,* 168.2* (s, CO₂ t-Bu), 197.7 (s, C=O); * signals with higher intensity.

HRMS (ESI, 80 eV): m/z calcd for C₁₆H₂₆O₅Na⁺: 321.1678; found: 321.1669; m/z calcd for C₁₆H₂₆O₅K⁺: 337.1417; found: 337.1418.

Anal. Calcd for C₁₆H₂₆O₅ (298.4): C, 64.41; H, 8.78. Found: C, 64.46; H, 9.20.

Di(tert-butyl) 3-Oxo-5-phenyl-4-pentene-1,1-dicarboxylate (5)

Following GP 1, phosphorane 1 (3.53 g, 10 mmol), di(tert-butyl) malonate (4.33 g, 20 mmol), NaH (0.48 g, 20 mmol), and NaI (1.51 g, 10 mmol) in DMF/THF (103 mL/21 mL) were used in the alkylation step. For the subsequent Wittig reaction freshly distilled benzaldehyde (1.91 g, 18 mmol) in CH₂Cl₂ (14 mL) was employed. The solvent was removed in vacuo and the residue was dissolved in CH₂Cl₂ (20 mL) and H₂O (300 mL) was added. The aqueous phase was extracted with pentane (3 × 15 mL) and the combined organic phases were washed with H₂O (2 × 15 mL) and dried (Na₂SO₄). After filtration, the solvents were removed in vacuo and the crude product (5.01 g, E:Z = 97:3) was purified by column chromatography (silica gel, Hex/EA 8:1) to provide two fractions (1: mixture of 5, di(tert)butyl malonate, benzaldehyde; 2: 1.04 g, 5 as colorless oil). From the first fraction pure product 5 (1.29 g) was obtained by removal of the volatile starting materials by Kugelrohr distillation. Combined yield of 5: 2.33 g (65%, E:Z >97:3).

IR (film): 3050 (=C–H), 2980 (C–H), 1740 (CO₂ t-Bu), 1695 (C=O), 1670 cm^–1 (Ph, C=C).

¹H NMR (CDCl₃, 300 MHz): δ = 1.48 (s, 18 H, 2 × CO₂ t-Bu), 3.22 (d, J = 7 Hz, 2 H, 2-H), 3.81 (t, J = 7 Hz, 1 H, 1-H), 6.75, 7.60 (2 d, J = 16.5 Hz, 1 H each, 5-H, 6-H), 7.38–7.41, 7.52–7.56 (2 m, 3 H, 2 H, Ph).

¹³C NMR (CDCl₃, 75.5 MHz): δ = 39.3 (t, C-2), 49.1 (d, C-1), 125.7, 128.3*, 128.9*, 130.6, 134.4 (4 d, s, C-4, Ph), 143.2 (d, C-5), 27.9*, 81.7*, 168.3* (q, 2 s, 2 × CO₂ t-Bu), 196.7 (s, C=O); * signals with higher intensity.

Anal. Calcd for C₂₁H₂₈O₅ (360.4): C, 69.99; H, 7.83. Found: C, 69.50; H, 8.05.

Di(tert-butyl) 6-(tert-Butyldimethylsiloxy)-3-oxo-4-hexene-1,1-dicarboxylate (6)

Following GP 1, phosphorane 1 (1.76 g, 5.00 mmol), di(tert-butyl) malonate (1.62 g, 7.50 mmol), NaH (0.132 g, 5.50 mmol), and NaI (0.750 g, 5.00 mmol) in DMF/THF (52 mL/10 mL) were used in the alkylation step. For the subsequent Wittig reaction tert-(butyldimethylsiloxy)acetaldehyde[18] (0.945 g, 5.42 mmol) in CH₂Cl₂ (40 mL) was employed. The solvent was removed in vacuo and the residue was dissolved in CH₂Cl₂ (20 mL) and H₂O (150 mL) was added. The aqueous phase was extracted with pentane (3 × 15 mL) and the combined organic phases were washed with H₂O (2 × 15 mL) and dried (Na₂SO₄­). After filtration, the solvents were removed in vacuo and the crude product (4.03 g, E:Z = 89:11) was purified by column chromatography (silica gel, Hex/EA 7:1) to provide pure (E)-6 (1.23 g, 57%) as a colorless oil.

IR (film): 3000 (=C–H), 2980 (C–H), 1740 (CO₂ t-Bu), 1700 (C=O), 1640 cm^–1 (C=C).

¹H NMR (CDCl₃, 300 MHz): δ = 0.08 (s, 6 H, SiMe₂), 0.91 (s, 9 H, Sit-Bu­), 1.45 (s, 18 H, 2 × CO₂ t-Bu), 3.11 (d, J = 7 Hz, 2 H, 2-H), 3.74 (t, J = 7 Hz, 1 H, 1-H), 4.36 (dd, J = 2, 3.5 Hz, 2 H, 6-H), 6.39 (td, J = 2, 16 Hz, 1 H, 4-H), 6.71 (td, J = 3.5, 16 Hz, 1 H, 5-H).

¹³C NMR (CDCl₃, 75.5 MHz): δ = –5.5* (q, SiMe₂), 25.8 (q, Sit-Bu), 39.1 (t, C-2), 48.9 (d, C-1), 62.2 (t, C-6), 127.2 (d, C-4), 146.1 (d, C-5), 27.9*, 81.7*, 168.3* (q, 2 s, 2 × CO₂ t-Bu), 196.6 (s, C=O); * signals with higher intensity.

Anal. Calcd for C₂₂H₄₀O₆Si (428.6): C, 61.65; H, 9.41. Found: C, 61.95; H, 9.74.

Di(tert-butyl) 5-(2-Furyl)-3-oxo-4-pentene-1,1-dicarboxylate (7)

Following GP 1, phosphorane 1 (2.01 g, 5.71 mmol), di(tert-butyl) malonate (2.47 g, 11.4 mmol), NaH (0.274 g, 11.4 mmol), and NaI (0.856 g, 5.71 mmol) in DMF/THF (58 mL/12 mL) were used in the alkylation step. For the subsequent Wittig reaction freshly distilled furan-2-carbaldehyde (0.823 g, 8.57 mmol) in CH₂Cl₂ (45 mL) was employed. The solvent was removed in vacuo and the residue was dissolved in CH₂Cl₂ (20 mL) and H₂O (170 mL) was added. The aqueous phase was extracted with pentane (3 × 15 mL) and the combined organic phases were washed with H₂O (2 × 15 mL) and dried (Na₂SO₄). After filtration, the solvents were removed in vacuo and the crude product (4.47 g, E:Z = 97:3) was purified by column chromatography (silica gel, Hex/EA 5:1) to provide three fractions [1: 0.046 g, E:Z = 30:70; 2: 1.04 g only (E)-7 as yellow oil; 3: 0.436 g of a mixture containing 0.305 g (E)-7]. The third fraction was again purified by chromatography (conditions as above) to give another 0.278 g of (E)-7. Combined yield of 7: 1.36 g (68%, E:Z = 99:1).

IR (film): 3050 (=C–H), 2980 (C–H), 1745 (CO₂ t-Bu), 1690 (C=O), 1615 cm^–1 (C=C).

Signals of (E)-7

¹H NMR (CDCl₃, 500 MHz): δ = 1.45 (s, 18 H, 2 × CO₂ t-Bu), 3.13 (d, J = 7 Hz, 2 H, 2-H), 3.78 (t, J = 7 Hz, 1 H, 1-H), 6.63 (d, J = 16 Hz, 1 H, 4-H), 7.34 (d, J = 16 Hz, 1 H, 5-H), 6.47, 6.65, 7.48 (m_c, d, br d, J = 3 Hz, J = 1.5 Hz, 3 H, furyl).

¹³C NMR (CDCl₃, 125.8 MHz): δ = 39.7 (t, C-2), 49.1 (d, C-1), 122.9 (d, C-4), 129.2 (d, C-5), 112.5, 115.9, 145.0, 150.9 (3 d, s, furyl), 27.9*, 81.7*, 168.3* (q, 2 s, 2 × CO₂ t-Bu), 196.2 (s, C=O); * signals with higher intensity.

Signals assigned to (Z)-7

¹H NMR (CDCl₃, 300 MHz): δ = 1.46 (s, 18 H, 2 × CO₂ t-Bu), 3.20 (d, J = 7 Hz, 2 H, 2-H), 3.88 (t, J = 7 Hz, 1 H, 1-H), 6.04 (d, J = 12.5 Hz, 1 H, 4-H).

Anal. Calcd for C₁₉H₂₆O₆ (350.4): C, 65.13; H, 7.48. Found: C, 64.98; H, 7.56.

Di(tert-butyl) 5-Ethoxycarbonyl-3-oxo-4-hexene-1,1-dicarboxylate (8)

Following GP 1, phosphorane 1 (1.91 g, 5.41 mmol), di(tert-butyl) malonate (1.76 g, 8.12 mmol), NaH (0.214 g, 8.93 mmol), and NaI (0.811 g, 5.41 mmol) in DMF/THF (60 mL/11 mL) were used in the alkylation step. For the subsequent Wittig reaction ethyl pyruvate (0.943 g, 8.12 mmol) in CH₂Cl₂ (45 mL) was employed. The solvent was removed in vacuo and the residue was dissolved in CH₂Cl₂ (20 mL) and H₂O (160 mL) was added. The aqueous phase was extracted with pentane (3 × 15 mL) and the combined organic phases were washed with H₂O (2 × 15 mL) and dried (Na₂SO₄). After filtration, the solvents were removed in vacuo and the crude product (4.02 g, E:Z = 91:9) was purified by column chromatography (silica gel, Hex/EA 5:1) to provide three fractions [1: 1.34 g, (E)-8 only; 2: 0.238 g E:Z = 41:59 as yellow oil; 3: 0.436 g of a mixture containing 0.305 g of (E)- 8]. The third fraction was again purified by chromatography (conditions as above) to give 0.278 g of (E)-8. Combined yield of 8: 1.58 g (79%, E:Z = 91:9).

IR (film): 3000 (=C–H), 2980 (C–H), 1745–1720 (CO₂ t-Bu, CO₂Et), 1700 (C=O), 1625 cm^–1 (C=C).

Signals of (E)-8

¹H NMR (CDCl₃, 500 MHz): δ = 1.31 (t, J = 7 Hz, 3 H, CH ₃CH₂O), 1.44 (s, 18 H, 2 × CO₂ t-Bu), 2.19 (br s, 3 H, 5-Me), 3.07 (d, J = 7 Hz, 2 H, 2-H), 3.72 (t, J = 7 Hz, 1 H, 1-H), 4.24 (q, J = 7 Hz, 2 H, CH₃CH ₂O), 7.08 (m_c, 1 H, 4-H).

¹³C NMR (CDCl₃, 125.8 MHz): δ = 14.1, 14.5 (2 q, C-6, CO₂Et), 43.2 (t, C-2), 48.9 (d, C-1), 131.4 (d, C-4), 141.6 (s, C-5), 61.6, 167.4 (t, s, CO₂Et), 27.9*, 81.9*, 167.9* (q, 2 s, 2 × CO₂ t-Bu), 198.2 (s, C=O); * signals with higher intensity.

Signals assigned to (Z)-8

¹H NMR (CDCl₃, 300 MHz): δ = 1.24–1.35 (m, 3 H, CH ₃CH₂O), 1.44 (s, 18 H, 2 × CO₂ t-Bu), 2.01 (br s, 3 H, 5-Me), 3.01 (d, J = 7 Hz, 2 H, 2-H), 3.70 (t, J = 7 Hz, 1 H, 1-H), 4.19–4.28* (m, 2 H, CH₃CH ₂O), 6.19 (m_c, 1 H, 4-H); * signal overlaps with those of (E)-8.

Anal. Calcd for C₁₉H₃₀O₇ (370.4): C, 61.61; H, 8.16. Found: C, 61.87; H, 8.29.

Synthesis of Enone 4 via Wittig–Horner Reaction with Phosphonate 11

Dimethyl 4,4-Di(tert-butoxycarbonyl)-2-ethoxy-1-butenylphosphonate (10)

To a suspension of NaH (0.125 g, 5.20 mmol) in THF (10 mL) was added dropwise at 0 °C di(tert-butyl) malonate (1.08 g, 5.00 mmol). After stirring for 1 h at r.t., the mixture was again cooled to 0 °C and phosphonic ester 9 (1.63 g, 6.00 mmol) was added. After stirring for 1 h at 0 °C and 16 h at r.t., the solvent was removed in vacuo and the residue was dissolved in CH₂Cl₂. This solution was washed with brine (2 ×), the organic phase was dried (Na₂SO₄), and the solvents were removed in vacuo. The resulting crude product 10 (1.94 g, 95%) was obtained as a yellow oil and was directly used in the next step.

IR (film): 1745–1730 (CO₂ t-Bu), 1615 (C=C), 1370–1355 (P–O–CH₃), 1250 (P=O), 1170 (P–O–Alkyl), 1030 cm^–1 (C–O).

¹H NMR (CDCl₃, 300 MHz): δ = 1.28 (t, J = 7 Hz, 3 H, OCH₂CH ₃), 1.43 (s, 18 H, 2 × CO₂ t-Bu), 3.10 (dd, J_PH  = 1.5 Hz, J_HH  = 7.5 Hz, 2 H, 3-H), 3.50 (t, J = 7.5 Hz, 1 H, 4-H), 3.69 [d, J_PH  = 11 Hz, 6 H, P(OMe)₂], 3.76 (q, J = 7 Hz, 2 H, OCH ₂CH₃), 4.40 (d, J_PH  = 6 Hz, 1 H, 1-H).

¹³C NMR (CDCl₃, 75.5 MHz): δ = 13.8 (q, OCH₂ CH₃), 31.6 (t, C-3), 51.9 (d, C-4), 52.5 [dq, J_CP  = 14.5 Hz, P(O)(OMe)₂], 63.9 (t, OCH₂CH₃), 82.5 (dd, J_CP  = 191 Hz, C-1), 27.9*, 81.9*, 167.9 (q, 2 s, 2 × CO₂ t-Bu), 171.9 (s, C-2); * signals with higher intensity.

Dimethyl 4,4-(Di-tert-butoxycarbonyl)-2-oxobutylphosphonate (11)

To a solution of phosphonic ester 10 (1.94 g, 4.75 mmol) in acetone (145 mL) were added at r.t. dropwise 1 N aq HCl (4.75 mL). After stirring for 1 h, the mixture was quenched with solid K₂CO₃ and the solvent was removed in vacuo. The residue was suspended in CH₂Cl₂ and the mixture was washed with sat. aq NaHCO₃ solution (2 ×). The organic phase was dried (Na₂SO₄) and the solvent was removed in vacuo to give crude 11 (1.59 g, 88%) as a brownish oil that was directly used in the next step.

IR (film): 1725 (CO₂ t-Bu, C=O), 1395–1340 (P–O–CH₃), 1260 (P=O), 1165 cm^–1 (P–O–Alkyl).

¹H NMR (CDCl₃, 300 MHz): δ = 1.43 (s, 18 H, 2 × CO₂ t-Bu), 3.14 (d, J = 7 Hz, 2 H, 3-H), 3.65 (t, J = 7 Hz, 1 H, 4-H), 3.75 (d, J_PH  = 11.5 Hz, 2 H, 1-H), 3.77 [d, J_PH  = 11 Hz, 6 H, P(OMe)₂].

¹³C NMR (CDCl₃, 75.5 MHz): δ = 41.2 (t, J_CP  = 128 Hz, C-1), 42.5 (t, C-3), 49.1 (d, C-4), 53.0 [dq, J_CP  = 12 Hz, P(O)(OMe)₂], 27.9*, 81.9*, 167.8 (q, 2 s, 2 × CO₂ t-Bu), 198.8 (s, C=O); * signals with higher intensity.

Enone 4

To freshly dried LiCl (0.042 g, 1.00 mmol) in CH₃CN (10 mL) were subsequently added at r.t. phosphonate 11 (0.380 g, 1.00 mmol), DIPEA (0.130 g, 1.00 mmol), and freshly distilled acetaldehyde (0.440 g, 10.0 mmol). The mixture was stirred for 22 h and then quenched with 2 N aq HCl. After extraction with Et₂O (3 × 20 mL), the combined organic phases were dried (Na₂SO₄), filtered, and all volatiles were removed in vacuo. The crude product was purified by column chromatography (silica gel, Hex/EA 8:1) to provide 4 (0.184 g, 62%) as a colorless oil.

Synthesis of Trienones 13–18 by Alkylation of Compounds 2–8 with Sorbyl Bromide (12); General Procedure 2 (GP 2)

To a suspension of NaH (1.0–1.5 equiv) in DMF and THF (5:1) was added at 0 °C the corresponding enone (1.0 equiv). After stirring for 1 h at r.t., the mixture was again cooled to 0 °C, and sorbyl bromide (12; 1.5 equiv) was added. The mixure was stirred for 16 h at r.t. and subsequently quenched with sat. aq NH₄Cl solution. The aqueous phase was extracted with Et₂O (3 × 20 mL) and the combined organic phases were washed with brine und subsequently dried (Na₂SO₄). After removal of the solvents in vacuo, the crude product was purified as described in the individual experiments.

Dimethyl (E,E,E)-4-Oxo-2,8,10-dodecatriene-6,6-dicarboxylate (13)

Following GP 2, enone 2 (0.150 g, 0.70 mmol), NaH (0.017 g, 0.70 mmol), and 12 (0.169 g, 1.05 mmol) in DMF/THF (5 mL/2 mL) provided the crude product (0.177 g). Flash chromatography (silica gel, Hex/EA 5:1) gave product 13 (0.085 g, 41%) as a colorless oil.

IR (film): 3100 (=C–H), 2950–2850 (C–H), 1740 (CO₂Me), 1700 (C=O), 1645 cm^–1 (C=C).

¹H NMR (CDCl₃, 200 MHz): δ = 1.68 (d, J = 6 Hz, 3 H, 12-H), 1.86 (dd, J = 2, 7 Hz, 3 H, 1-H), 2.74 (d, J = 7 Hz, 2 H, 7-H), 3.17 (s, 2 H, 5-H), 3.69 (s, 6 H, 2 × CO₂Me), 5.21–5.65 (m, 2 H, 8-H, 11-H), 5.89–5.98 (m, 2 H, 10-H, 9-H), 6.05 (qd, J = 2, 16 Hz, 1 H, 3-H), 6.84 (qd, J = 7, 16 Hz, 1 H, 2-H).

¹³C NMR (CDCl₃, 50.3 MHz): δ = 17.9, 18.1 (2 q, C-12, C-1), 36.5 (t, C-7), 42.4 (t, C-5), 55.2 (s, C-6), 124.4, 128.8, 131.0, 131.6, 134.9 (5 d, C-11, C-10, C-9, C-8, C-3), 143.2 (d, C-2), 52.5*, 170.9* (q, s, CO₂Me), 196.4 (s, C-4); * signals with higher intensity.

Anal. Calcd for C₁₆H₂₂O₅ (294.3): C, 65.30; H, 7.53. Found: C, 65.15; H, 7.58.

Di(tert-butyl) (E,E,E)-4-Oxo-2,8,10-dodecatriene-6,6-dicarboxylate (14)

Following GP 2, enone 4 (0.480 g, 1.61 mmol), NaH (0.047 g, 1.94 mmol), and 12 (0.390 g, 2.42 mmol) in DMF/THF (13 mL/2.5 mL) provided the crude product (0.582 g). Chromatography (silica gel, Hex/EA 8:1) gave product 14 (0.468 g, 77%) as a yellow oil.

IR (film): 3020 (=C–H), 2980 (C–H), 1730 (CO₂ t-Bu), 1690 (C=O), 1650 cm^–1 (C=C).

¹H NMR (CDCl₃, 500 MHz): δ = 1.41 (s, 18 H, 2 × CO₂ t-Bu), 1.69 (br d, J = 6.7 Hz, 3 H, 12-H), 1.86 (dd, J = 1.6, 6.8 Hz, 3 H, 1-H), 2.68 (d, J = 7.8 Hz, 2 H, 7-H), 3.08 (s, 2 H, 5-H), 5.31 (td, J = 7.8, 13.8 Hz, 1 H, 8-H), 5.53 (qd, J = 6.7, 13.8 Hz, 1 H, 11-H), 5.85–5.99 (m, 2 H, 10-H, 9-H), 6.07 (qd, J = 1.6, 15.8 Hz, 1 H, 3-H), 6.83 (qd, J = 6.8, 15.8 Hz, 1 H, 2-H).

¹³C NMR (CDCl₃, 100 MHz): δ = 18.0 (q, C-12), 18.2 (q, C-1), 36.0 (t, C-7), 41.9 (t, C-5), 56.4 (s, C-6), 125.2 (d, C-8), 128.3 (d, C-11), 131.2, 134.5 (2 d, C-9, C-10), 132.0 (d, C-3), 142.9 (d, C-2), 27.8, 81.4, 169.5 (q, 2 s, 2 × CO₂ t-Bu), 196.9 (s, C-4).

HRMS (ESI, 80 eV): m/z calcd for C₂₂H₃₄O₅Na⁺: 401.2340; found: 401.2328; m/z calcd for C₂₂H₃₄O₅K⁺: 417.2043; found: 417.2089.

Anal. Calcd for C₂₂H₃₄O₅ (378.5): C, 69.91; H, 9.05. Found: C, 69.42; H, 9.49.

Di(tert-butyl) (E,E,E)-4-Oxo-1-phenyl-1,7,9-undecatriene-5,5-dicarboxylate (15)

Following GP 2, enone 5 (0.851 g, 2.36 mmol), NaH (0.064 g, 2.68 mmol), and 12 (0.540 g, 3.35 mmol) in THF (25 mL) provided the crude product (1.13 g). Chromatography (silica gel, Hex/EA 8:1) gave product 15 (0.515 g, 50%) as a colorless solid; mp 104–106 °C.

IR (KBr): 2980–2930 (=C–H, C–H), 1750 (CO₂ t-Bu), 1695 (C=O), 1650, 1615 cm^–1 (C=C).

¹H NMR (CDCl₃, 300 MHz): δ = 1.45 (s, 18 H, 2 × CO₂ t-Bu), 1.68 (d, J = 6 Hz, 3 H, 10-Me), 3.25 (s, 2 H, 4-H), 5.35–5.39, 5.48–5.55 (2 m, 2 H, 7-H, 10-H), 5.95–6.00 (m, 2 H, 8-H, 9-H), 6.69 (d, J = 16 Hz, 1 H, 2-H), 7.51–7.54, 7.37–7.40 (2 m, 3 H, 2 H, Ph), 7.55 (d, J = 16 Hz, 1 H, 1-H).

¹³C NMR (CDCl₃, 75.5 MHz): δ = 17.9 (q, 10-Me), 36.2 (t, C-6), 42.8 (t, C-4), 56.7 (s, C-5), 125.2, 126.4, 128.5, 130.5, 131.1, 134.6 (6 d, C-2, C-7, C-8, C-9, C-10, Ph), 128.3*, 128.9*, 134.5 (2 d, s, Ph), 142.7 (d, C-1), 27.8, 81.50*, 169.5* (q, 2 s, 2 × CO₂ t-Bu), 196.9 (s, C=O); * signals with higher intensity.

Anal. Calcd for C₂₇H₃₆O₅ (440.5): C, 73.62; H, 8.24. Found: C, 73.89; H, 8.39.

Di(tert-butyl) (E,E,E)-1-(tert-Butyldimethylsiloxy)-4-oxo-2,8,10-dodecatriene-6,6-dicarboxylate (16)

Following GP 2, enone 6 (0.387 g, 0.903 mmol), NaH (0.025 g, 1.08 mmol), and 12 (0.216 g, 1.34 mmol) in DMF/THF (5 mL/1 mL) provided the crude product (0.405 g). Chromatography (silica gel, Hex/EA 5:1) gave product 16 (0.264 g, 57%) as a colorless oil.

IR (film): 3000 (=C–H), 2980–2955 (C–H), 1730 (CO₂ t-Bu), 1680 (C=O), 1640 cm^–1 (C=C).

¹H NMR (CDCl₃, 300 MHz): δ = 0.07 (s, 6 H, 2 × SiMe₂), 0.91 (s, 9 H, Sit-Bu), 1.44 (s, 18 H, 2 CO₂ t-Bu), 1.70 (d, J = 6.5 Hz, 3 H, 12-Me), 2.71 (d, J = 7.5 Hz, 2 H, 7-H), 3.13 (s, 2 H, 5-H), 4.33 (br dd, J = 2, 3.5 Hz, 2 H, 1-H), 5.31–5.35, 5.51–5.58 (2 m, 1 H each, 8-H, 11-H), 5.93–5.98 (m, 2 H, 9-H, 10-H), 6.33 (br td, J = 2, 15.5 Hz, 1 H, 3-H), 6.85 (td, J = 3.5, 15.5 Hz, 1 H, 2-H).

¹³C NMR (CDCl₃, 75.5 MHz): δ = –5.4* (q, SiMe₂), 17.9 (q, C-12), 25.6 (q, Sit-Bu), 35.9 (t, C-7), 42.6 (t, C-5), 56.5 (s, C-6), 62.2 (t, C-1), 125.3, 127.8, 128.4, 131.2, 134.5 (5 d, C-8, C-9, C-10, C-11, C-3), 145.5 (d, C-2), 27.8*, 81.4*, 169.5* (q, 2 s, 2 × CO₂ t-Bu), 196.8 (s, C=O); * signals with higher intensity.

Anal. Calcd for C₂₈H₄₈O₆Si (508.8): C, 66.09; H, 9.51. Found: C, 66.61; H, 9.87.

Di(tert-butyl) (E,E,E)-1-(2-Furyl)-3-oxo-1,7,9-undecatriene-5,5-dicarboxylate (17)

Following GP 2, enone 7 (1.04 g, 2.97 mmol), NaH (0.107 g, 4.45 mmol), and 12 (0.717 g, 4.45 mmol) in DMF/THF (27 mL/5.5 mL) provided the crude product (1.34 g). Chromatography (silica gel, Hex/EA 10:1) gave product 17 (0.859 g, 67%) as a yellow solid; mp 107–110 °C.

IR (KBr): 3000 (=C–H), 2980–2970 (C–H), 1750 (CO₂ t-Bu), 1660 (C=O), 1650 cm^–1 (C=C).

¹H NMR (CDCl₃, 300 MHz): δ = 1.43 (s, 18 H, 2 × CO₂ t-Bu), 1.68 (d, J = 6 Hz, 3 H, 10-Me), 2.72 (d, J = 7.5 Hz, 2 H, 6-H), 3.17 (s, 2 H, 4-H), 5.28–5.38, 5.50–5.55 (2 m, 1 H each, 7-H, 10-H), 5.93–5.97 (m, 2 H, 8-H, 9-H), 6.58, 7.29 (2 d, J = 16 Hz, 1 H each, 1-H, 2-H), 6.47, 6.62, 7.47 (dd, 2 d, J = 1.5, 3.5 Hz, J = 1.5 Hz, J = 3.5 Hz, 3 H, furyl).

¹³C NMR (CDCl₃, 125.8 MHz): δ = 17.9 (q, C-11), 36.1 (t, C-6), 43.1 (t, C-4), 56.7 (s, C-5), 123.6 (d, C-2), 125.2, 128.4 (2 d, C-7, C-10), 128.8 (d, C-1), 131.1, 134.6 (2 d, C-8, C-9), 112.5, 115.8, 144.9, 151.0 (3 d, s, furyl-C), 27.8*, 81.5*, 169.5* (q, 2 s, 2 × CO₂ t-Bu), 196.5 (s, C=O); * signals with higher intensity.

Anal. Calcd for C₂₅H₃₄O₆ (430.5): C, 69.75; H, 7.96. Found: C, 69.54; H, 7.94.

Di(tert-butyl) (E,E,E)-2-Ethoxycarbonyl-4-oxo-2,8,10-dodecatriene-6,6-dicarboxylate (18)

Following GP 2, enone 8 (0.300 g, 0.810 mmol), NaH (0.023 g, 0.972 mmol), and 12 (0.196 g, 1.21 mmol) in DMF/THF (7 mL/1.5 mL) provided the crude product (0.813 g). Chromatography (silica gel, Hex/EA 5:1) gave product 18 (0.236 g, 65%) as a colorless solid; mp 62–65 °C.

IR (KBr): 3000 (=C–H), 2980 (C–H), 1750 (CO₂ t-Bu, CO₂Et), 1700 (C=O), 1625 cm^–1 (C=C).

¹H NMR (CDCl₃, 300 MHz): δ = 1.31 (t, J = 7 Hz, 3 H, OCH₂CH ₃), 1.43 (s, 18 H, 2 × CO₂ t-Bu), 1.70 (d, J = 6.5 Hz, 3 H, 11-Me), 2.17 (d, J = 1.5 Hz, 3 H, 1-H), 2.71 (d, J = 7.5 Hz, 2 H, 7-H), 3.11 (s, 2 H, 5-H), 4.24 (q, J = 7 Hz, 2 H, OCH ₂CH₃), 5.31–5.35, 5.52–5.59 (2 m, 1 H each, 8-H, 11-H), 5.93–5.98 (m, 2 H, 9-H, 10-H), 7.02 (q, J = 1.5 Hz, 1 H, 3-H).

¹³C NMR (CDCl₃, 75.5 MHz): δ = 14.1, 14.3, 17.9 (3 q, C-1, C-12, OCH₂ CH₃), 36.2 (t, C-7), 46.6 (t, C-5), 56.7 (s, C-6), 125.1, 128.6, 131.1, 132.1, 134.6 (5 d, C-3, C-8, C-9, C-10, C-11), 140.9 (s, C-2), 61.5, 167.5 (t, s, CO₂ CH₂CH₃), 27.8*, 81.6*, 169.2* (q, 2 s, 2 × CO₂ t-Bu), 198.5 (s, C=O); * signals with higher intensity.

Anal. Calcd for C₂₅H₃₈O₇ (450.6): C, 66.65; H, 8.50. Found: C, 66.86; H, 8.67.

Di(tert-butyl) (E)-7-(2-Furyl-4-oxo-2-heptene-6,6-dicarboxylate (20)

Analogously to GP 2, enone 4 (0.363 g, 1.22 mmol), NaH (0.035 g, 1.46 mmol), and 2-furylmethyl bromide 19 (0.295 g, 1.82 mmol) in DMF/THF (13 mL/2.5 mL) provided the crude product (0.857 g). Chromatography (silica gel, Hex/EA 8:1) gave product 20 (0.268 g, 58%) as a yellow oil.

IR (film): 3000 (=C–H), 2980–2935 (C–H), 1730 (CO₂ t-Bu), 1680 (C=O), 1635 cm^–1 (C=C).

¹H NMR (CDCl₃, 300 MHz): δ = 1.44 (s, 18 H, 2 × CO₂ t-Bu), 1.87 (dd, J = 1.5, 7 Hz, 3 H, 1-H), 3.07 (s, 2 H, 5-H), 3.38 (s, 2 H, 7-H), 5.95–5.96 (m, 1 H, furyl), 6.07 (dd, J = 1.5, 16 Hz, 1 H, 3-H), 6.22–6.24 (m, 1 H, furyl), 6.81 (dq, J = 7, 16 Hz, 1 H, 2-H), 7.24–7.25 (m, 1 H, furyl).

¹³C NMR (CDCl₃, 125.8 MHz): δ = 18.2 (q, C-1), 30.9 (t, C-7), 41.9 (t, C-5), 56.3 (s, C-6), 131.9, 141.7 (2 d, C-3, C-2), 108.2, 110.1, 142.8, 151.6 (3 d, s, furyl-C), 27.9*, 81.6*, 168.9* (q, 2 s, 2 × CO₂ t-Bu), 196.9 (s, C=O); * signals with higher intensity.

Anal. Calcd for C₂₁H₃₀O₆ (378.4): C, 66.66; H, 7.99. Found: C, 66.58; H, 7.93.

Synthesis of Compound 13 via Tosylate 22; Formation of Bicyclic Side-Product 23

Preparation of Solution A: To a suspension of NaH (53 mg, 2.21 mmol) in DMF/THF (20 mL/4 mL) was added at 0 °C enone 4 (529 mg, 1.77 mmol) and the mixture was stirred for 50 min at r.t.

Preparation of Solution B: In a second flask (E,E)-hexa-2,4-dien-1-ol (869 mg, 8.85 mmol) in THF (15 mL) at –78 °C was treated with n-BuLi (3.55 mL, 2.5 M in Hex, 8.85 mmol). After stirring for 10 min, tosyl chloride (1.69 g, 8.85 mmol) in THF (20 mL) was added and the solution was stirred for 70 min at –78 °C. This solution was added within 15 min via a dry ice cooled cannula to solution A and the resulting mixture was stirred for 16 h at 0 °C. After quenching with brine (50 mL), the formed precipitate was dissolved by the addition of H₂O (20 mL). Then Et₂O (20 mL) was added and the aqueous phase was extracted with Et₂O (2 × 20 mL). The combined organic phases were dried (Na₂SO₄) and all volatiles were removed in vacuo. The crude product (2.02 g) was purified by column chromatography (silica gel, Hex/EA 8:1) to provide a 1:1 mixture of 14 and 23 (368 mg, calculated yields 21% and 42%). By a second chromatography (conditions as above) 23 could be separated from 14. After repeated recrystallization from Et₂O, suitable crystals for an X-ray crystal structure analysis were obtained.

Di(tert-butyl) (2R*,3aR*,4R*,6aR*)-Hexahydro-2-{bis[(tert-butyl)oxycarbonyl]methyl}-4-methyl-3-oxo-6a-[(E)-1-propen-1-yl]­-cyclopenta[b]furan-5,5-dicarboxylate (23)

Colorless solid; mp 143–145 °C.

IR (KBr): 3010 (=C–H), 2975–2870 (C–H), 1745 (C=O), 1725 cm^–1 (C=O).

¹H NMR (CDCl₃, 500 MHz): δ = 1.06 (d, J = 7.3 Hz, 3 H, 4-Me), 1.41, 1.42 (2 s, 9 H each, 2 × CO₂ t-Bu), 1.40, 1.47 (2 s, 9 H each, 5-CO₂ t-Bu), 1.71 (dd, J = 1.5, 6.5 Hz, 3 H, 3′-H), 2.32 (d, J = 4.8 Hz, 1 H, 3a-H), 2.34, 2.55 (2 d, J = 14.9 Hz, 1 H each, 6-H), 3.05 (dq, J = 4.8, 7.3 Hz, 1 H, 4-H), 3.50 (d, J = 9.0 Hz, 1 H, 1′′-H), 4.39 (d, J = 9.0 Hz, 1 H, 2-H), 5.47 (qd, J = 1.5, 15.3 Hz, 1 H, 1′-H), 5.87 (qd, J = 6.5, 15.3 Hz, 1 H, 2′-H).

¹³C NMR (CDCl₃, 100 MHz): δ = 17.5 (q, C-3′), 17.6 (q, 4-Me), 27.8, 28.0 (2 q, 5-CO₂ t-Bu), 27.85, 27.86 (2 q, 1′′-CO₂ t-Bu), 41.7 (d, C-4), 45.3 (t, C-6), 54.6 (d, C-1′′), 62.6 (d, C-3a), 65.5 (s, C-5), 78.2 (d, C-2), 81.2, 81.83, 81.87, 81.91 (4 s, CO₂ t-Bu), 89.5 (s, C-6a), 125.2 (d, C-2′), 131.0 (d, C-1′), 165.2, 165.6 (2 s, 1′′-CO₂ t-Bu), 168.9, 170.3 (2 s, 5-CO₂ t-Bu), 211.7 (s, C-3).

MS (EI, 80 eV, 110 °C): m/z (%) = 594 (0.5, [M]⁺), 538 (3, [M – C₄H₈]⁺), 482 (13, [M – 2 C₄H₈]⁺), 465 (1, [M – C₄H₈ – C₄H₈O]⁺), 426 (72, [M – 3 C₄H₈]⁺), 409 (16, [M – 2 C₄H₈ – C₄H₈O]⁺), 370 (88, [M – 4 C₄H₈]⁺), 353 (56, [M – 3 C₄H₈ – C₄H₈O]⁺), 266 (26), 210 (55), 165 (51), 164 (57), 57 (100, [C₄H₉]⁺).

HRMS (ESI, 80 eV): m/z calcd for C₃₂H₅₀O₁₀Na⁺: 617.3302; found: 617.3218; m/z calcd for C₃₂H₅₀O₁₀K⁺: 633.3041; found: 633.2947.

Anal. Calcd for C₃₂H₅₀O₁₀ (594.7): C, 64.62; H, 8.47. Found: C, 64.40; H, 7.91.

Crystal Data

C₃₂H₅₀O₁₀, M_r = 594.72, triclinic, P-1, a = 10.233(3), b = 12.591(3), c = 14.436(4) Å, α = 83.548(5)°, β = 81.065(5)°, γ = 69.288(5)°, V = 1715.3(8) ų, Z = 2, ρ_c = 1.151 g cm^–3, μ = 0.083 mm^–1 Mo_Kα, λ = 0.71073 Å, T = 133 K, 18134 measured reflexions, 6013 unique reflexions and 4778 observed reflexions with I > 2σ(I), R_int = 0.0267, The structure was solved by direct methods, a final refinement on F² with 393 parameters converged at wR(F²) = 0.1075, R(F) = 0.0381.[19] [20]

Acknowledgment

Generous support by the Deutsche Forschungsgemeinschaft, the Arzneimittelwerk Dresden, and Bayer HealthCare is most gratefully acknowledged. We also thank Regina Czerwonka and Luise Schefzig for experimental help.

• References


Reviews:
• 1a Brieger G, Bennett JN. Chem. Rev. 1980; 80: 63
  CrossrefSearch in Google Scholar
• 1b Roush WR. Intramolecular Diels–Alder Reactions . In Comprehensive Organic Synthesis . Vol. 5. Trost BM, Fleming I. Elsevier; Amsterdam: 1991: 513
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Selected recent examples:
• 2a O’Leary-Steele C, Pedersen PJ, James T, Lanyon-Hogg T, Leach S, Hayes J, Nelson A. Chem. Eur. J. 2010; 16: 9563
  CrossrefSearch in Google Scholar
• 2b Abdelkafi H, Evanno L, Deville A, Dubost L, Chiaroni A, Nay B. Eur. J. Org. Chem. 2011; 2789
• 2c Ross AG, Li X, Danishefsky SJ. J. Am. Chem. Soc. 2012; 134: 16080
  CrossrefSearch in Google Scholar
• 2d Ramanathan M, Tan C.-J, Chang W.-J, Tsai H.-HG, Hou D.-R. Org. Biomol. Chem. 2013; 11: 3846
  CrossrefSearch in Google Scholar
• 2e Han J.-C, Liu L.-Z, Chang Y.-Y, You G.-Z, Guo J, Zhou L.-Y, Li C.-C, Yang Z. J. Org. Chem. 2013; 78: 5492
  CrossrefSearch in Google Scholar
• 2f Gärtner M, Satyanarayana G, Förster S, Helmchen G. Chem. Eur. J. 2013; 19: 400
  CrossrefSearch in Google Scholar
• 2g Wang Y, Rogachev V, Wolter M, Gruner M, Jäger A, Metz P. Eur. J. Org. Chem. 2014; 4083
• 2h Usui K, Suzuki T, Nakada M. Tetrahedron Lett. 2015; 56: 1247
  CrossrefSearch in Google Scholar
• 3a Zschiesche R, Grimm EL, Reissig H.-U. Angew. Chem., Int. Ed. Engl. 1986; 25: 1086 ; Angew. Chem. 1986, 98, 1104
  CrossrefSearch in Google Scholar
• 3b Zschiesche R, Frey B, Grimm E, Reissig H.-U. Chem. Ber. 1990; 123: 363
  CrossrefSearch in Google Scholar
• 3c Frey B, Hünig S, Koch M, Reissig H.-U. Synlett 1991; 854
  Thieme Connect
• 3d Frey B, Schnaubelt J, Reissig H.-U. Eur. J. Org Chem. 1999; 1377
• 3e Frey B, Schnaubelt J, Reissig H.-U. Eur. J. Org. Chem. 1999; 1385
• 3f Schnaubelt J, Frey B, Reissig H.-U. Helv. Chim. Acta 1999; 82: 666
  CrossrefSearch in Google Scholar
• 3g Frey B, Reissig H.-U. J. Prakt. Chem. 1999; 341: 173
  Search in Google Scholar

Reviews:
• 4a Reissig H.-U. Top. Curr. Chem. 1988; 144: 73
  Search in Google Scholar
• 4b Reissig H.-U, Zimmer R. Chem. Rev. 2003; 103: 1151
  Search in Google Scholar
• 5 Hudson RF, Chopard PA. J. Org. Chem. 1963; 28: 2446
  CrossrefSearch in Google Scholar
• 6 Piers E, Abeysekara B. Can. J. Chem. 1982; 60: 1114
  CrossrefSearch in Google Scholar
• 7a Blanchette MA, Choy W, Davis JT, Essenfeld AP, Masamune S, Roush WR, Sakai T. Tetrahedron Lett. 1984; 25: 2183
  CrossrefSearch in Google Scholar
• 7b Rathke MW, Nowak M. J. Org. Chem. 1985; 50: 2624
  CrossrefSearch in Google Scholar
• 8 Review: Johnson CD. Acc. Chem. Res. 1993; 26: 476
  CrossrefSearch in Google Scholar
• 9a Jacobson M. J. Am. Chem. Soc. 1955; 77: 2461
  CrossrefSearch in Google Scholar
• 9b Mori K. Tetrahedron 1974; 30: 3807
  CrossrefSearch in Google Scholar
• 9c Kim T, Mirafzal GA, Liu J, Bauld N. J. Am. Chem. Soc. 1993; 115: 7653
  CrossrefSearch in Google Scholar
• 10 Woodward RB. J. Am. Chem. Soc. 1940; 62: 1478
  CrossrefSearch in Google Scholar
• 11 Bäckvall JE, Nilsson YI. M, Andersson PG. J. Am. Chem. Soc. 1993; 115: 6609
  CrossrefSearch in Google Scholar
• 12 Andersson PG, Bäckvall JE. J. Org. Chem. 1991; 56: 5349
  Search in Google Scholar
• 13 Burke LT, Dixon DJ, Ley SV, Rodríguez F. Org. Biomol. Chem. 2005; 3: 274
  CrossrefPubMedSearch in Google Scholar
• 14 Farrugia LJ. J. Appl. Crystallogr. 1997; 30: 565
  Search in Google Scholar
• 15 As an alternative, deprotonated 4 may first add to enone 4 followed by reaction with tosyl chloride to introduce an additional double bond, double-cyclization and protonation to 23. Currently, there are no arguments available favoring or disfavoring this mechanistic scenario.

Selected examples for the use of phosphorane 1 for the synthesis of heterocycles or enones, see:
• 16a Flitsch W, Hohenhorst M. Liebigs Ann. Chem. 1990; 397
• 16b Caballero E, Guilhot F, López JL, Medarde M, Sahagún H, Tomé F. Tetrahedron Lett. 1996; 37: 6951
  CrossrefSearch in Google Scholar
• 16c Alajarí M, Cabrera J, Pastor A, Sánchez-Andrada P, Bautista D. J. Org. Chem. 2008; 73: 963
  CrossrefSearch in Google Scholar
• 16d Sieng B, Ventura OL, Bellosta V, Cossy J. Synlett 2008; 1216
  Thieme Connect
• 16e Sasaki M, Oyamada K, Takeda K. J. Org. Chem. 2010; 75: 3941
  CrossrefSearch in Google Scholar
• 16f Clark JS, Romiti F, Sieng B, Paterson LC, Stewart A, Chaudhury S, Thomas LH. Org. Lett. 2015; 17: 4694
  CrossrefSearch in Google Scholar
• 17 Thiemermann J.; Schnaubelt, J.; Zimmer, R.; Reissig, H.-U. Manuscript in preparation.
• 18a Reetz MT, Peter R. Tetrahedron Lett. 1981; 22: 4691
  CrossrefSearch in Google Scholar
• 18b Enders D, Schüßeler T. Synthesis 2002; 2280
  Thieme Connect
• 19 Sheldrick GM. Acta Crystallogr., Sect. A 2008; 64: 112
  CrossrefPubMedSearch in Google Scholar
• 20 CCDC 1483329 (23) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif or by writing to the Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: (internat.) +44 1223 336 033; E-mail: deposit@ccdc.cam.ac.uk.

• References


Reviews:
• 1a Brieger G, Bennett JN. Chem. Rev. 1980; 80: 63
  CrossrefSearch in Google Scholar
• 1b Roush WR. Intramolecular Diels–Alder Reactions . In Comprehensive Organic Synthesis . Vol. 5. Trost BM, Fleming I. Elsevier; Amsterdam: 1991: 513
  CrossrefSearch in Google Scholar
• 1c Takao K, Munakata R, Tadano K. Chem. Rev. 2005; 105: 4779
  CrossrefPubMedSearch in Google Scholar
• 1d Juhl M, Tanner D. Chem. Soc. Rev. 2009; 38: 2983
  CrossrefPubMedSearch in Google Scholar

Selected recent examples:
• 2a O’Leary-Steele C, Pedersen PJ, James T, Lanyon-Hogg T, Leach S, Hayes J, Nelson A. Chem. Eur. J. 2010; 16: 9563
  CrossrefSearch in Google Scholar
• 2b Abdelkafi H, Evanno L, Deville A, Dubost L, Chiaroni A, Nay B. Eur. J. Org. Chem. 2011; 2789
• 2c Ross AG, Li X, Danishefsky SJ. J. Am. Chem. Soc. 2012; 134: 16080
  CrossrefSearch in Google Scholar
• 2d Ramanathan M, Tan C.-J, Chang W.-J, Tsai H.-HG, Hou D.-R. Org. Biomol. Chem. 2013; 11: 3846
  CrossrefSearch in Google Scholar
• 2e Han J.-C, Liu L.-Z, Chang Y.-Y, You G.-Z, Guo J, Zhou L.-Y, Li C.-C, Yang Z. J. Org. Chem. 2013; 78: 5492
  CrossrefSearch in Google Scholar
• 2f Gärtner M, Satyanarayana G, Förster S, Helmchen G. Chem. Eur. J. 2013; 19: 400
  CrossrefSearch in Google Scholar
• 2g Wang Y, Rogachev V, Wolter M, Gruner M, Jäger A, Metz P. Eur. J. Org. Chem. 2014; 4083
• 2h Usui K, Suzuki T, Nakada M. Tetrahedron Lett. 2015; 56: 1247
  CrossrefSearch in Google Scholar
• 3a Zschiesche R, Grimm EL, Reissig H.-U. Angew. Chem., Int. Ed. Engl. 1986; 25: 1086 ; Angew. Chem. 1986, 98, 1104
  CrossrefSearch in Google Scholar
• 3b Zschiesche R, Frey B, Grimm E, Reissig H.-U. Chem. Ber. 1990; 123: 363
  CrossrefSearch in Google Scholar
• 3c Frey B, Hünig S, Koch M, Reissig H.-U. Synlett 1991; 854
  Thieme Connect
• 3d Frey B, Schnaubelt J, Reissig H.-U. Eur. J. Org Chem. 1999; 1377
• 3e Frey B, Schnaubelt J, Reissig H.-U. Eur. J. Org. Chem. 1999; 1385
• 3f Schnaubelt J, Frey B, Reissig H.-U. Helv. Chim. Acta 1999; 82: 666
  CrossrefSearch in Google Scholar
• 3g Frey B, Reissig H.-U. J. Prakt. Chem. 1999; 341: 173
  Search in Google Scholar

Reviews:
• 4a Reissig H.-U. Top. Curr. Chem. 1988; 144: 73
  Search in Google Scholar
• 4b Reissig H.-U, Zimmer R. Chem. Rev. 2003; 103: 1151
  Search in Google Scholar
• 5 Hudson RF, Chopard PA. J. Org. Chem. 1963; 28: 2446
  CrossrefSearch in Google Scholar
• 6 Piers E, Abeysekara B. Can. J. Chem. 1982; 60: 1114
  CrossrefSearch in Google Scholar
• 7a Blanchette MA, Choy W, Davis JT, Essenfeld AP, Masamune S, Roush WR, Sakai T. Tetrahedron Lett. 1984; 25: 2183
  CrossrefSearch in Google Scholar
• 7b Rathke MW, Nowak M. J. Org. Chem. 1985; 50: 2624
  CrossrefSearch in Google Scholar
• 8 Review: Johnson CD. Acc. Chem. Res. 1993; 26: 476
  CrossrefSearch in Google Scholar
• 9a Jacobson M. J. Am. Chem. Soc. 1955; 77: 2461
  CrossrefSearch in Google Scholar
• 9b Mori K. Tetrahedron 1974; 30: 3807
  CrossrefSearch in Google Scholar
• 9c Kim T, Mirafzal GA, Liu J, Bauld N. J. Am. Chem. Soc. 1993; 115: 7653
  CrossrefSearch in Google Scholar
• 10 Woodward RB. J. Am. Chem. Soc. 1940; 62: 1478
  CrossrefSearch in Google Scholar
• 11 Bäckvall JE, Nilsson YI. M, Andersson PG. J. Am. Chem. Soc. 1993; 115: 6609
  CrossrefSearch in Google Scholar
• 12 Andersson PG, Bäckvall JE. J. Org. Chem. 1991; 56: 5349
  Search in Google Scholar
• 13 Burke LT, Dixon DJ, Ley SV, Rodríguez F. Org. Biomol. Chem. 2005; 3: 274
  CrossrefPubMedSearch in Google Scholar
• 14 Farrugia LJ. J. Appl. Crystallogr. 1997; 30: 565
  Search in Google Scholar
• 15 As an alternative, deprotonated 4 may first add to enone 4 followed by reaction with tosyl chloride to introduce an additional double bond, double-cyclization and protonation to 23. Currently, there are no arguments available favoring or disfavoring this mechanistic scenario.

Selected examples for the use of phosphorane 1 for the synthesis of heterocycles or enones, see:
• 16a Flitsch W, Hohenhorst M. Liebigs Ann. Chem. 1990; 397
• 16b Caballero E, Guilhot F, López JL, Medarde M, Sahagún H, Tomé F. Tetrahedron Lett. 1996; 37: 6951
  CrossrefSearch in Google Scholar
• 16c Alajarí M, Cabrera J, Pastor A, Sánchez-Andrada P, Bautista D. J. Org. Chem. 2008; 73: 963
  CrossrefSearch in Google Scholar
• 16d Sieng B, Ventura OL, Bellosta V, Cossy J. Synlett 2008; 1216
  Thieme Connect
• 16e Sasaki M, Oyamada K, Takeda K. J. Org. Chem. 2010; 75: 3941
  CrossrefSearch in Google Scholar
• 16f Clark JS, Romiti F, Sieng B, Paterson LC, Stewart A, Chaudhury S, Thomas LH. Org. Lett. 2015; 17: 4694
  CrossrefSearch in Google Scholar
• 17 Thiemermann J.; Schnaubelt, J.; Zimmer, R.; Reissig, H.-U. Manuscript in preparation.
• 18a Reetz MT, Peter R. Tetrahedron Lett. 1981; 22: 4691
  CrossrefSearch in Google Scholar
• 18b Enders D, Schüßeler T. Synthesis 2002; 2280
  Thieme Connect
• 19 Sheldrick GM. Acta Crystallogr., Sect. A 2008; 64: 112
  CrossrefPubMedSearch in Google Scholar
• 20 CCDC 1483329 (23) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif or by writing to the Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: (internat.) +44 1223 336 033; E-mail: deposit@ccdc.cam.ac.uk.

• Supplementary Material