Synthesis and Olfactory Properties of Seco-Analogues of Lilac Aldehydes

Lilac aldehydes are considered as principal olfactory molecules of lilac flowers. We have designed, prepared, and evaluated a set of racemic seco-analogues of such natural products. The synthesis employs commercially available α-chloroketones as substrates that are transformed in four steps to target compounds. Their qualitative olfactory analysis revealed that the opening of the tetrahydrofuran ring leads to a vanishing of original flowery scent with the emergence of spicy aroma accompanied by green notes, and/or fruity aspects of novel seco-analogues. These results suggest the important osmophoric role of THF moiety for the generation of the typical flowery aroma associated with lilac aldehydes.


Introduction
Lilac aldehydes 1 ( Figure 1) were first isolated in 1974 from an oil [1] of lilac flowers (Syringa vulgaris L., Oleaceae). Being considered as important phytovolatiles, structure elucidation and olfactometric analysis of all stereoisomers was performed [2]. Consequently, the biosynthesis of lilac aldehydes was proposed and investigated [3]. Since then, these naturally occurring monoterpenes were found in flowers of many other species, including kiwifruit [4], the White Campion [5], and the Lesser Butterfly orchid [6]. Thus, fragrant lilac aldehydes represent an attractive olfactory target for insect pollinators. It is known that these flower-scenting molecules are much sought after by (nocturnal) moth species [7][8][9], butterflies [10,11], and even mosquitos [12][13][14]. In this context, lilac aldehydes are being developed as chemical markers of the botanical origin of honeys [15][16][17][18]. Interestingly, lilac aldehydes were recently found as odour-active compounds in oysters, and thus, could be potentially used as freshness indicators for this delicacy [19]. For perfumery purposes, synthetically prepared lilac aldehydes are used almost exclusively. Interestingly, the major naturally occurring (5 S)-stereoisomers 1a-d have a lower odour threshold by 1-2 orders of magnitude in comparison to lilac aldehydes 1e-h with (5 R)absolute configuration [2] ( Figure 1).
Up to date, numerous syntheses of racemic [4,8,[20][21][22][23][24][25] and enantiomerically pure lilac aldehydes 1 are known [2,[26][27][28]. Recently, we have published the first comprehensive study investigating the importance of respective substituents on the genuine flowery odour of lilac aldehydes. We have found [29] that the addition of methyl group to C-2 stereogenic centre of lilac aldehydes 1 significantly shifts the original flowery odour to a rather herbal scent of their unnatural homologues 2. In addition, various functional groups have only minimal effect on the scent variations ( Figure 2).
As a continuation of our research, we decided to investigate the influence of tetrahydrofuran ring and/or alkene moiety on the olfactory properties of C-2 methylated homologues of lilac aldehydes 2. Thus, we have devised a new set of (racemic) seco-analogues 3-7 featuring a higher conformational freedom and/or variable substitution pattern of the C=C bond ( Figure 3).

Results and Discussion
The preparation of novel seco-analogues 3-7 features a common synthetic strategy that starts with an acid-catalysed ketalisation of commercially available α-chloroketones 8-11 with neopentyl glycol followed by elimination of intermediary chloroketals 12-15 under basic conditions [30]. Unlike the chlorocyclopentane ketal 14, the elimination of chlorocyclohexane ketal 15 provided an inseparable mixture of desired cyclohexene ketal 19 and its regioisomer 25 in a ratio of 5:1 (based on the integration of respective olefinic signals in 1 H NMR spectrum). Thus, the obtained alkenyl ketals 16-19 were reductively opened either by diisobutyl aluminium hydride [31] or methyl magnesium bromide [32] to furnish the corresponding alcohols 20-24. In case of DIBAL reduction of mixture of ketals 19 + 25, only 19 was opened while 25 remained untouched under the reaction conditions. This enabled the efficient FLC separation of unreacted ketal 25 from desired alcohol 24. Eventually, the final Dess-Martin oxidation [33] of pure alcohols 20-24 provided target aldehydes 3-7 in overall yields of 2-21% over four steps (Scheme 1). With seco-analogues of lilac aldehydes 3-7 in our hands, we have undertaken their qualitative sensory evaluation. Since lilac alcohols also contribute to the complex scent of lilac flowers, we have also included their acyclic analogues 20-24 in the olfactory screening. The results are summarised in Table 1. Evidently, the opening of the tetrahydrofuran ring leads to a vanishing of flowery scent typical for lilac aldehydes 1, suggesting the important olfactophoric role of THF moiety. Thus, ring-opened analogues 3-5 bearing an acyclic alkene exhibit a rather common spicy, sharp aroma with green/herbal notes. The scent of their congeners featuring a cyclic alkene is further shifted towards sweet, fruity aspects for 6 and herbal, green notes for 7. Interestingly and for comparison, while the respective alcohols 20, 22, 23, and 24 commonly exhibit sweet(ish) aroma with oily/fatty and turpentine-like facets, alcohol 21 features a pleasant balsamic aroma with mintyeucalypty notes. Finally, the odour intensity for target compounds was rather weak to moderate with only short aroma persistence in a range of tens of minutes.

Materials and Methods
Chemicals and reagents were purchased from commercial sources (Alfa Aesar, Sigma-Aldrich) and were used without further purification. Anhydrous solvents were prepared by distillation and standing over activated 4Å molecular sieves under argon atmosphere. Hexanes refer to a mixture of C-6 alkanes (b.p. 60-80 °C). Yields refer to chromatographically and spectroscopically ( 1 H NMR) homogeneous material, unless otherwise stated. Reactions were monitored by thin layer chromatography (TLC) carried out on aluminium sheets pre-coated with silica gel 60 F254 (Merck). Visualisation was performed using shortwave UV light followed by dipping TLC plates in either basic solution of KMnO4, acidic solution of vanillin or acidic solution of ceric ammonium nitrate followed by heating with a heat gun. Preparative thin layer chromatography (PTLC) was carried out on glass plates (20 × 20 cm) coated with PLC silica gel 60 (layer thickness 1 mm) with concentrating zone (20 × 4 cm). Flash column chromatography (FLC) was performed using Silica Gel 60 (particle size 40-63 μm). Medium-pressure liquid chromatography (MPLC) was performed on Büchi Sepacor System equipped with Pump Module C-615 and Fraction Collector C-660 using silica gel (particle size 15-40 μm). NMR spectra were recorded in CDCl3 on a Varian INOVA 300 (300 MHz for 1 H, 75 MHz for 13 C nuclei), Varian 400-MR (399.9 MHz for 1 H, 100.6 MHz for 13 C nuclei) or Varian VNMRS 600 (600 MHz for 1 H, 151 MHz for 13 C nuclei) NMR spectrometer and were correctly shifted using residual non-deuterated solvent as an internal reference (CHCl3: δH = 7.26 ppm, δC = 77.16 ppm (central peak of a 1:1:1 triplet). Chemical shifts (δ) are quoted in ppm. Liquid chromatography-mass spectrometry (LC-MS) analyses were performed on Agilent 1200 Series instrument equipped with a multimode MS detector using the MM ESI/APCI ionisation method (column Zorbax Eclipse XDB-18, 150 × 4.6 mm, particle size 5 μm, eluent water with 0.1% HCO2H/CH3CN, 70:30, flow 1.5 mL/min). High-resolution mass spectra (HR-MS) were recorded on a Thermo Scientific Orbitrap Velos mass spectrometer with a heated electrospray ionisation (HESI) source in positive and/or negative mode. FTIR spectra were obtained on a Nicolet 5700 spectrometer (Thermo Electron) equipped with a Smart Orbit (diamond crystal ATR) accessory using the reflectance technique (4000-400 cm -1 ). The sensory analysis was performed by authors in a clean and odourless environment at 22 °C by using testing strips of odourless absorbent paper. This was wetted with the tested compound and the paper strip was smelled at certain intervals, while the scent was recorded.

Materials and Methods
Chemicals and reagents were purchased from commercial sources (Alfa Aesar, Sigma-Aldrich) and were used without further purification. Anhydrous solvents were prepared by distillation and standing over activated 4Å molecular sieves under argon atmosphere. Hexanes refer to a mixture of C-6 alkanes (b.p. 60-80 °C). Yields refer to chromatographically and spectroscopically ( 1 H NMR) homogeneous material, unless otherwise stated. Reactions were monitored by thin layer chromatography (TLC) carried out on aluminium sheets pre-coated with silica gel 60 F254 (Merck). Visualisation was performed using shortwave UV light followed by dipping TLC plates in either basic solution of KMnO4, acidic solution of vanillin or acidic solution of ceric ammonium nitrate followed by heating with a heat gun. Preparative thin layer chromatography (PTLC) was carried out on glass plates (20 × 20 cm) coated with PLC silica gel 60 (layer thickness 1 mm) with concentrating zone (20 × 4 cm). Flash column chromatography (FLC) was performed using Silica Gel 60 (particle size 40-63 μm). Medium-pressure liquid chromatography (MPLC) was performed on Büchi Sepacor System equipped with Pump Module C-615 and Fraction Collector C-660 using silica gel (particle size 15-40 μm). NMR spectra were recorded in CDCl3 on a Varian INOVA 300 (300 MHz for 1 H, 75 MHz for 13 C nuclei), Varian 400-MR (399.9 MHz for 1 H, 100.6 MHz for 13 C nuclei) or Varian VNMRS 600 (600 MHz for 1 H, 151 MHz for 13 C nuclei) NMR spectrometer and were correctly shifted using residual non-deuterated solvent as an internal reference (CHCl3: δH = 7.26 ppm, δC = 77.16 ppm (central peak of a 1:1:1 triplet). Chemical shifts (δ) are quoted in ppm. Liquid chromatography-mass spectrometry (LC-MS) analyses were performed on Agilent 1200 Series instrument equipped with a multimode MS detector using the MM ESI/APCI ionisation method (column Zorbax Eclipse XDB-18, 150 × 4.6 mm, particle size 5 μm, eluent water with 0.1% HCO2H/CH3CN, 70:30, flow 1.5 mL/min). High-resolution mass spectra (HR-MS) were recorded on a Thermo Scientific Orbitrap Velos mass spectrometer with a heated electrospray ionisation (HESI) source in positive and/or negative mode. FTIR spectra were obtained on a Nicolet 5700 spectrometer (Thermo Electron) equipped with a Smart Orbit (diamond crystal ATR) accessory using the reflectance technique (4000-400 cm -1 ). The sensory analysis was performed by authors in a clean and odourless environment at 22 °C by using testing strips of odourless absorbent paper. This was wetted with the tested compound and the paper strip was smelled at certain intervals, while the scent was recorded.

Materials and Methods
Chemicals and reagents were purchased from commercial sources (Alfa Aesar, Sigma-Aldrich) and were used without further purification. Anhydrous solvents were prepared by distillation and standing over activated 4Å molecular sieves under argon atmosphere. Hexanes refer to a mixture of C-6 alkanes (b.p. 60-80 °C). Yields refer to chromatographically and spectroscopically ( 1 H NMR) homogeneous material, unless otherwise stated. Reactions were monitored by thin layer chromatography (TLC) carried out on aluminium sheets pre-coated with silica gel 60 F254 (Merck). Visualisation was performed using shortwave UV light followed by dipping TLC plates in either basic solution of KMnO4, acidic solution of vanillin or acidic solution of ceric ammonium nitrate followed by heating with a heat gun. Preparative thin layer chromatography (PTLC) was carried out on glass plates (20 × 20 cm) coated with PLC silica gel 60 (layer thickness 1 mm) with concentrating zone (20 × 4 cm). Flash column chromatography (FLC) was performed using Silica Gel 60 (particle size 40-63 μm). Medium-pressure liquid chromatography (MPLC) was performed on Büchi Sepacor System equipped with Pump Module C-615 and Fraction Collector C-660 using silica gel (particle size 15-40 μm). NMR spectra were recorded in CDCl3 on a Varian INOVA 300 (300 MHz for 1 H, 75 MHz for 13 C nuclei), Varian 400-MR (399.9 MHz for 1 H, 100.6 MHz for 13 C nuclei) or Varian VNMRS 600 (600 MHz for 1 H, 151 MHz for 13 C nuclei) NMR spectrometer and were correctly shifted using residual non-deuterated solvent as an internal reference (CHCl3: δH = 7.26 ppm, δC = 77.16 ppm (central peak of a 1:1:1 triplet). Chemical shifts (δ) are quoted in ppm. Liquid chromatography-mass spectrometry (LC-MS) analyses were performed on Agilent 1200 Series instrument equipped with a multimode MS detector using the MM ESI/APCI ionisation method (column Zorbax Eclipse XDB-18, 150 × 4.6 mm, particle size 5 μm, eluent water with 0.1% HCO2H/CH3CN, 70:30, flow 1.5 mL/min). High-resolution mass spectra (HR-MS) were recorded on a Thermo Scientific Orbitrap Velos mass spectrometer with a heated electrospray ionisation (HESI) source in positive and/or negative mode. FTIR spectra were obtained on a Nicolet 5700 spectrometer (Thermo Electron) equipped with a Smart Orbit (diamond crystal ATR) accessory using the reflectance technique (4000-400 cm -1 ). The sensory analysis was performed by authors in a clean and odourless environment at 22 °C by using testing strips of odourless absorbent paper. This was wetted with the tested compound and the paper strip was smelled at certain intervals, while the scent was recorded.

Materials and Methods
Chemicals and reagents were purchased from commercial sources (Alfa Aesar, Sigma-Aldrich) and were used without further purification. Anhydrous solvents were prepared by distillation and standing over activated 4Å molecular sieves under argon atmosphere. Hexanes refer to a mixture of C-6 alkanes (b.p. 60-80 °C). Yields refer to chromatographically and spectroscopically ( 1 H NMR) homogeneous material, unless otherwise stated. Reactions were monitored by thin layer chromatography (TLC) carried out on aluminium sheets pre-coated with silica gel 60 F254 (Merck). Visualisation was performed using shortwave UV light followed by dipping TLC plates in either basic solution of KMnO4, acidic solution of vanillin or acidic solution of ceric ammonium nitrate followed by heating with a heat gun. Preparative thin layer chromatography (PTLC) was carried out on glass plates (20 × 20 cm) coated with PLC silica gel 60 (layer thickness 1 mm) with concentrating zone (20 × 4 cm). Flash column chromatography (FLC) was performed using Silica Gel 60 (particle size 40-63 μm). Medium-pressure liquid chromatography (MPLC) was performed on Büchi Sepacor System equipped with Pump Module C-615 and Fraction Collector C-660 using silica gel (particle size 15-40 μm). NMR spectra were recorded in CDCl3 on a Varian INOVA 300 (300 MHz for 1 H, 75 MHz for 13 C nuclei), Varian 400-MR (399.9 MHz for 1 H, 100.6 MHz for 13 C nuclei) or Varian VNMRS 600 (600 MHz for 1 H, 151 MHz for 13 C nuclei) NMR spectrometer and were correctly shifted using residual non-deuterated solvent as an internal reference (CHCl3: δH = 7.26 ppm, δC = 77.16 ppm (central peak of a 1:1:1 triplet). Chemical shifts (δ) are quoted in ppm. Liquid chromatography-mass spectrometry (LC-MS) analyses were performed on Agilent 1200 Series instrument equipped with a multimode MS detector using the MM ESI/APCI ionisation method (column Zorbax Eclipse XDB-18, 150 × 4.6 mm, particle size 5 μm, eluent water with 0.1% HCO2H/CH3CN, 70:30, flow 1.5 mL/min). High-resolution mass spectra (HR-MS) were recorded on a Thermo Scientific Orbitrap Velos mass spectrometer with a heated electrospray ionisation (HESI) source in positive and/or negative mode. FTIR spectra were obtained on a Nicolet 5700 spectrometer (Thermo Electron) equipped with a Smart Orbit (diamond crystal ATR) accessory using the reflectance technique (4000-400 cm -1 ). The sensory analysis was performed by authors in a clean and odourless environment at 22 °C by using testing strips of odourless absorbent paper. This was wetted with the tested compound and the paper strip was smelled at certain intervals, while the scent was recorded.

Materials and Methods
Chemicals and reagents were purchased from commercial sources (Alfa Aesar, Sigma-Aldrich) and were used without further purification. Anhydrous solvents were prepared by distillation and standing over activated 4Å molecular sieves under argon atmosphere. Hexanes refer to a mixture of C-6 alkanes (b.p. 60-80 °C). Yields refer to chromatographically and spectroscopically ( 1 H NMR) homogeneous material, unless otherwise stated. Reactions were monitored by thin layer chromatography (TLC) carried out on aluminium sheets pre-coated with silica gel 60 F254 (Merck). Visualisation was performed using shortwave UV light followed by dipping TLC plates in either basic solution of KMnO4, acidic solution of vanillin or acidic solution of ceric ammonium nitrate followed by heating with a heat gun. Preparative thin layer chromatography (PTLC) was carried out on glass plates (20 × 20 cm) coated with PLC silica gel 60 (layer thickness 1 mm) with concentrating zone (20 × 4 cm). Flash column chromatography (FLC) was performed using Silica Gel 60 (particle size 40-63 μm). Medium-pressure liquid chromatography (MPLC) was performed on Büchi Sepacor System equipped with Pump Module C-615 and Fraction Collector C-660 using silica gel (particle size 15-40 μm). NMR spectra were recorded in CDCl3 on a Varian INOVA 300 (300 MHz for 1 H, 75 MHz for 13 C nuclei), Varian 400-MR (399.9 MHz for 1 H, 100.6 MHz for 13 C nuclei) or Varian VNMRS 600 (600 MHz for 1 H, 151 MHz for 13 C nuclei) NMR spectrometer and were correctly shifted using residual non-deuterated solvent as an internal reference (CHCl3: δH = 7.26 ppm, δC = 77.16 ppm (central peak of a 1:1:1 triplet). Chemical shifts (δ) are quoted in ppm. Liquid chromatography-mass spectrometry (LC-MS) analyses were performed on Agilent 1200 Series instrument equipped with a multimode MS detector using the MM ESI/APCI ionisation method (column Zorbax Eclipse XDB-18, 150 × 4.6 mm, particle size 5 μm, eluent water with 0.1% HCO2H/CH3CN, 70:30, flow 1.5 mL/min). High-resolution mass spectra (HR-MS) were recorded on a Thermo Scientific Orbitrap Velos mass spectrometer with a heated electrospray ionisation (HESI) source in positive and/or negative mode. FTIR spectra were obtained on a Nicolet 5700 spectrometer (Thermo Electron) equipped with a Smart Orbit (diamond crystal ATR) accessory using the reflectance technique (4000-400 cm -1 ). The sensory analysis was performed by authors in a clean and odourless environment at 22 °C by using testing strips of odourless absorbent paper. This was wetted with the tested compound and the paper strip was smelled at certain intervals, while the scent was recorded.

Materials and Methods
Chemicals and reagents were purchased from commercial sources (Alfa Aesar, Sigma-Aldrich) and were used without further purification. Anhydrous solvents were prepared by distillation and standing over activated 4Å molecular sieves under argon atmosphere. Hexanes refer to a mixture of C-6 alkanes (b.p. 60-80 °C). Yields refer to chromatographically and spectroscopically ( 1 H NMR) homogeneous material, unless otherwise stated. Reactions were monitored by thin layer chromatography (TLC) carried out on aluminium sheets pre-coated with silica gel 60 F254 (Merck). Visualisation was performed using shortwave UV light followed by dipping TLC plates in either basic solution of KMnO4, acidic solution of vanillin or acidic solution of ceric ammonium nitrate followed by heating with a heat gun. Preparative thin layer chromatography (PTLC) was carried out on glass plates (20 × 20 cm) coated with PLC silica gel 60 (layer thickness 1 mm) with concentrating zone (20 × 4 cm). Flash column chromatography (FLC) was performed using Silica Gel 60 (particle size 40-63 μm). Medium-pressure liquid chromatography (MPLC) was performed on Büchi Sepacor System equipped with Pump Module C-615 and Fraction Collector C-660 using silica gel (particle size 15-40 μm). NMR spectra were recorded in CDCl3 on a Varian INOVA 300 (300 MHz for 1 H, 75 MHz for 13 C nuclei), Varian 400-MR (399.9 MHz for 1 H, 100.6 MHz for 13 C nuclei) or Varian VNMRS 600 (600 MHz for 1 H, 151 MHz for 13 C nuclei) NMR spectrometer and were correctly shifted using residual non-deuterated solvent as an internal reference (CHCl3: δH = 7.26 ppm, δC = 77.16 ppm (central peak of a 1:1:1 triplet). Chemical shifts (δ) are quoted in ppm. Liquid chromatography-mass spectrometry (LC-MS) analyses were performed on Agilent 1200 Series instrument equipped with a multimode MS detector using the MM ESI/APCI ionisation method (column Zorbax Eclipse XDB-18, 150 × 4.6 mm, particle size 5 μm, eluent water with 0.1% HCO2H/CH3CN, 70:30, flow 1.5 mL/min). High-resolution mass spectra (HR-MS) were recorded on a Thermo Scientific Orbitrap Velos mass spectrometer with a heated electrospray ionisation (HESI) source in positive and/or negative mode. FTIR spectra were obtained on a Nicolet 5700 spectrometer (Thermo Electron) equipped with a Smart Orbit (diamond crystal ATR) accessory using the reflectance technique (4000-400 cm -1 ). The sensory analysis was performed by authors in a clean and odourless environment at 22 °C by using testing strips of odourless absorbent paper. This was wetted with the tested compound and the paper strip was smelled at certain intervals, while the scent was recorded.
Herbal, slightly green, with earthy notes

Materials and Methods
Chemicals and reagents were purchased from commercial sources (Alfa Aesar, Sigma-Aldrich) and were used without further purification. Anhydrous solvents were prepared by distillation and standing over activated 4Å molecular sieves under argon atmosphere. Hexanes refer to a mixture of C-6 alkanes (b.p. 60-80 • C). Yields refer to chromatographically and spectroscopically ( 1 H NMR) homogeneous material, unless otherwise stated. Reactions were monitored by thin layer chromatography (TLC) carried out on aluminium sheets pre-coated with silica gel 60 F 254 (Merck). Visualisation was performed using shortwave UV light followed by dipping TLC plates in either basic solution of KMnO 4 , acidic solution of vanillin or acidic solution of ceric ammonium nitrate followed by heating with a heat gun. Preparative thin layer chromatography (PTLC) was carried out on glass plates (20 × 20 cm) coated with PLC silica gel 60 (layer thickness 1 mm) with concentrating zone (20 × 4 cm). Flash column chromatography (FLC) was performed using Silica Gel 60 (particle size 40-63 µm). Medium-pressure liquid chromatography (MPLC) was performed on Büchi Sepacor System equipped with Pump Module C-615 and Fraction Collector C-660 using silica gel (particle size 15-40 µm). NMR spectra were recorded in CDCl 3 on a Varian INOVA 300 (300 MHz for 1 H, 75 MHz for 13 C nuclei), Varian 400-MR (399.9 MHz for 1 H, 100.6 MHz for 13 C nuclei) or Varian VNMRS 600 (600 MHz for 1 H, 151 MHz for 13 C nuclei) NMR spectrometer and were correctly shifted using residual non-deuterated solvent as an internal reference (CHCl 3 : δ H = 7.26 ppm, δ C = 77.16 ppm (central peak of a 1:1:1 triplet). Chemical shifts (δ) are quoted in ppm. Liquid chromatography-mass spectrometry (LC-MS) analyses were performed on Agilent 1200 Series instrument equipped with a multimode MS detector using the MM ESI/APCI ionisation method (column Zorbax Eclipse XDB-18, 150 × 4.6 mm, particle size 5 µm, eluent water with 0.1% HCO 2 H/CH 3 CN, 70:30, flow 1.5 mL/min). High-resolution mass spectra (HR-MS) were recorded on a Thermo Scientific Orbitrap Velos mass spectrometer with a heated electrospray ionisation (HESI) source in positive and/or negative mode. FTIR spectra were obtained on a Nicolet 5700 spectrometer (Thermo Electron) equipped with a Smart Orbit (diamond crystal ATR) accessory using the reflectance technique (4000-400 cm -1 ). The sensory analysis was performed by authors in a clean and odourless environment at 22 • C by using testing strips of odourless absorbent paper. This was wetted with the tested compound and the paper strip was smelled at certain intervals, while the scent was recorded.

General Experiment for the Preparation of Chloroketals (12-15)
A stirred solution of chloroketone 8-11, 2,2-dimethyl-1,3-propanediol (1.0 or 1.2 equiv) and p-TsOH·H 2 O (0.023 equiv) in cyclohexane (c = 0.7 M) was refluxed in a round bottom flask equipped with a Dean-Stark apparatus. After the indicated time, the mixture was cooled to RT and solvent was evaporated in vacuo (bath temperature 50-55 • C, pressure 30-50 mbar) and the resulting oil dissolved in Et 2 O. The ethereal solution was sequentially washed with sat. aq. NaHCO 3 soln., water and brine, dried (MgSO 4 ) and concentrated in vacuo (35 • C, 30 mbar). The obtained crude product was further used as such or purified either by bulb-to-bulb vacuum distillation (Kugelrohr) or FLC to furnish a corresponding chloroketal 12-15. The structural characterization ( 1 H-NMR, 13   To a stirred solution of potassium hydroxide (11 eq.) in ethylene glycol was added to chloroketal 12-15 at 120 • C and the reaction mixture was heated at 160 • C for 7-23 h. After cooling to RT, water was added and extracted with Et 2 O. The organic phase was washed with water and brine, dried (MgSO 4 ) and concentrated in vacuo (35 • C, 30-200 mbar). The crude product was purified either by bulb-to-bulb vacuum distillation (Kugelrohr) or FLC to furnish a corresponding ketal 16-19, 25.  (21) 2,2-Dimethyl-3-(2-methyl-but-3-en-2-yloxy)propan-1-ol (21) To a stirred solution of ketal 16 (0.3 g, 1.9 mmol) in anhydrous toluene (32 mL) was added 3M solution of MeMgBr in diethyl ether (6.4 mL, 19.2 mmol, 10 equiv) drop-wise at 0 • C and the mixture was heated at 80 • C for 4 h under Ar. After cooling the mixture to 0 • C, the reaction was carefully quenched with sat. aq. NH 4 Cl soln. (25 mL) and water (10 mL). The layers were separated and the aqueous phase was extracted with Et 2 O (3 × 15 mL). The combined organic layers were washed with brine (30 mL) and dried over Na 2 SO 4 . The solvents were evaporated in vacuo (75 • C, 29 mbar) and crude material was purified by MPLC(16 g SiO 2 , flow 50 mL/min, fraction 5 mL, gradient elution hexanes/AcOEt 90:10 → 50:50) to furnish alcohol 21 (75 mg, 23%) as colourless oil; R f (hexanes/AcOEt 5:1) 0. To a stirred solution of ketal 16-18, anhydrous THF was added dropwise to a solution of DIBAL in toluene (1.0 M, 3-5 equiv) at 0 • C over 5-10 min under Ar. The mixture was warmed to 50 • C and stirred for 2-4.5 d. The cooled mixture (ice) was quenched with sat. aq. soln. of Rochelle salt and water, Et 2 O was added and stirred for 2-5 h at RT. The layers were separated and the aqueous phase was extracted with Et 2 O. The combined organic layers were washed with brine and dried over MgSO 4 . The solvents were evaporated in vacuo (73 • C, 30 mbar). The crude product was purified either by bulb-to-bulb vacuum distillation (Kugelrohr) or FLC to furnish a corresponding alcohol 20, 22, 23.