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Journal of the Brazilian Chemical Society

Print version ISSN 0103-5053

J. Braz. Chem. Soc. vol.10 no.1 São Paulo Jan./Feb. 1999

http://dx.doi.org/10.1590/S0103-50531999000100002 

Article

 

Synthesis of Analogues of 2-iodohexadecanal, a Regulator of Iodine Metabolism in the Thyroid Gland

 

Hugues Van den Bergen, Désiré Daloze, and Jean-Claude Braekman*

Laboratory of Bio-organic Chemistry (CP 160/07), Department of Organic Chemistry, Faculty of Sciences, University of Brussels, 50 Av.F.D.Roosevelt, 1050 Brussels, Belgium

 

 

Com o objetivo futuro de fazer um estudo da relação estrutura-atividade, foram sintetisados vários derivados do 2-iodo-hexadecanal [1], um regulador do metabolismo de iodo na glândula tireóide, que diferem no comprimento da cadeia, natureza do substituinte e grupo funcional terminal.
 
With the object of performing a structure-activity relationship study, we have synthesized several analogues of 2-iodohexadecanal [1], a regulator of iodine metabolism in the thyroid gland, differing by the chain length, the nature of the substituent, and/or the terminal functional group.
Keywords: a-halogenocarbonyl compounds, 2-iodohexadecanal

 

 

Introduction

As a part of a program dealing with the regulation of the thyroid gland metabolism by iodide, 2-iodohexadecanal [1] has been identified as a major iodolipid1. It is formed upon addition of iodine to the vinyl diethylether group of plasmalogens followed by hydrolysis1,2. The investigation of the biological activities of synthetic (±)-1 revealed its ability to inhibit both H2O2 production in cultured dog thyroid cells3 and the human thyroid adenylyl cyclase4. (2S)-1 and (2R)-1 exhibit identical biological activities, thus suggesting the lack of stereoselectivity in their interaction with the biological receptors5.

Prompted by these interesting findings, we decided to investigate the structural parameters of 1 required for observation of biological activities. Thus, a series of analogues of 1 differing by the chain length (n), the nature of the substituent (X) and that of the terminal function (Y) have been synthesized. The syntheses of these analogues, all of them new compounds, are presented in this paper.

 

 

Results and Discussion

Syntheses of 2-halogenoaldehydes 1-8, 2-iodohexadecanoic acid [18], methyl 2-iodohexadecanoate [19] and 2-iodohexadecanamide [22]

2-Iodoaldehydes 1-5 were synthesized by direct iodination of the corresponding long chain aldehydes using the mixture HgCl2/I2 (yield: 50-60%)6. In our hands, this method was superior to the alternative one passing through substitution of the bromine of 2-bromoaldehydes by iodine (NaI/CH3CN; yield 86%), as bromination of the n-aldehydes was only achieved with rather low yields. For example, 2-bromohexadecanal [6] was synthesized by direct bromination of n-hexadecanal with t-BuBr/DMSO in a 41% yield7.

n-Octanal and n-dodecanal are commercially available. n-Hexadecanal, n-octadecanal and n-eicosanal were synthesized by PCC oxidation of the corresponding alcohols in an 80-90% yield8.

2-Chlorohexadecanal [7] was synthesized in two steps by chlorination of n-hexadecanal dimethylacetal [24], using the mixture MnCl2/ MnO2 / TMSCl9 to afford 25 in 67% yield, followed by acid hydrolysis of 25 with CF3COOH/H2O/CH2Cl2 (yield 71%). We have found these a-chloroacetal hydrolysis conditions to be an efficient alternative to those described by Boni et al. (AcOH/HCl10 or Ac2O/AcCl/AcONa.3H2O11). Moreover, neither direct chlorination of n-hexadecanal [9] with SO2Cl212, or n-hexadecanal trimethylsilylenolether with Cl213 led to the formation of 2-chlorohexadecanal [7], probably because n-hexadecanal or 2-chlorohexadecanal polymerized under the reaction conditions.

Several methods have been described in the literature for the preparation of 2-fluoroaldehydes but they present significant drawbacks, such as poor yields or the need of fluorine gas14-18. Our approach to the synthesis of 2-fluoroaldehydes avoids these drawbacks. Our synthesis of 2-fluorohexadecanal [8] was based on a described synthesis of 2-fluorooctadecanoic acid19. Hexadecanoic acid [26] was brominated using the mixture P/Br2, esterified with methanol (yield: 67%), and the bromine of the resulting bromoester [27] exchanged by fluorine [AgF/ CH3CN/ H2O; yield: 50%)] to afford methyl 2-fluorohexadecanoate [29] (Scheme 2). Several attempts to reduce the ester function of 29 into an aldehyde using DIBAH under different reaction conditions (-78 °C; in hexane, diethylether, CH2Cl2 or toluene) always led to a mixture of the reactant and 2-fluorohexadecanol. Therefore, 29 was first reduced to 2-fluorohexadecanol in an 83% yield using LiAlH4, followed by Swern oxidation20 which cleanly afforded 2-fluorohexadecanal [8] in a 90% yield.

 

 

 

 

 

 

Methyl 2-iodohexadecanoate [19] was synthesized following two different procedures. 2-Iodohexadecanoic acid [18] was first prepared by direct iodination of hexadecanoic acid [26] using the mixture ClSO3H /I221. Addition of methanol to the reaction mixture afforded 19 in a 38% yield after purification by column chromatography on silica gel21. Alternatively, compound 19 was prepared by substitution of the bromine of methyl 2-bromohexadecanoate [27] using NaI in CH3CN (yield: 93%).

2-Iodohexadecanamide [22] was prepared by aminolysis of 27 with gaseous NH3 in MeOH-CHCl322 (yield: 55%), followed by substitution of the bromine by iodine which gave 2-iodohexadecanamide [22] in a 92% yield.

Synthesis of 2-mesyloxyhexadecanal [10]

The preparation of 2-mesyloxy-23 and 2-tosyloxyketones24 is already described but up to now, no method was available for the preparation of 2-mesyloxy- and 2-tosyloxyaldehydes. Attempts to prepare 2-tosyloxyhexadecanal by direct reaction of n-hexadecanal with HTIB25 only led to complex reaction mixtures. In contrast, the attempted reduction of 2-mesyloxyhexadecanenitrile with DIBAH led to the recovery of the starting material. We also failed to obtain 2-mesyloxyhexadecanal [10] by hydrolysis of the S,S-dioxydedithioketal26 or the dimethylketal of 2-mesyloxyhexadecanal27 probably due to the strong inductive effect of the mesyloxy group. Finally, 10 was synthesized starting from 1-hexadecene [30]. Dihydroxylation of 30 into 31 with OsO428 followed by selective protection of the primary hydroxyl group of 31 with TBDMSCl29, mesylation of the secondary hydroxyl group of 32 with MsCl30 and deprotection of the primary hydroxyl group of 33 with TFA31 led to 2-mesyloxyhexadecanol [34]. Swern oxidation20 of 34 gave 2-mesyloxyhexadecanal [10] which proved to be a relatively unstable compound.

Synthesis of 3-halogeno-2-ketones 11-14, and 17 and of 3-tosyloxy-2-nonanone [16]

3-Bromo-2-nonanone [12] was synthesized regiospecifically by direct bromination of 2-nonanone [15] with the system TMSBr/DMSO32.

3-Iodo-2-nonanone [11] was cleanly synthesized in a 77% yield by substitution of the bromine of 12 by NaI in CH3CN. In contrast with literature claims6, direct iodination of 2-nonanone [15] with HgCl2 and I2 was not regioselective and gave a mixture of 3-iodo-2-nonanone [11] and 1-iodo-2-nonanone (82:18), which have the same Rf on TLC in different eluent systems, together with small amounts of 1,3-diiodo-2-nonanone. The same problem of regioselectivity was encountered in the direct iodination of 2-heptadecanone (see below). Thus, the first method is superior to the second one because the bromination reaction is regiospecific.

3-Chloro-2-nonanone [13] was prepared in a 92% yield by direct chlorination of 2-nonanone [15] with MnO2/TMSCl in AcOH33. Another chlorinating system, TMSCl/DMSO in acetonitrile, is described for the introduction of a chlorine atom into the more substituted position of a ketone34. In our hands, the use of these conditions only led to 3-methylthio-2-nonanone in a 66% yield.

3-Fluoro-2-nonanone [14] was obtained by substitution of the bromine atom of 3-bromo-2-nonanone [12] with AgF19.

3-Tosyloxy-2-nonanone [16] was synthesized by direct oxidation of 2-nonanone [15] by HTIB25 which gave a mixture of 3-tosyloxy-2-nonanone [16] (yield: 30%) and 1-tosyloxy-2-nonanone (yield: 15%). The two compounds could be easily separated by flash chromatography.

3-Iodo-2-heptadecanone [17] was synthesized starting from hexadecan-1-ol. Oxidation of hexadecan-1-ol by PCC8, followed by addition of methylmagnesiumbromide, hydrolysis and PCC oxidation of the resulting 2-heptadecanol [35] gave 2-heptadecanone [36]. Iodination of the latter with HgCl2/I26 at rt. gave a 77:23 mixture of 3-iodo-2-heptadecanone [17] and 1-iodo-2-heptadecanone [33] (yield: 53%). A higher regioselectivity could be obtained at reflux (95:5; 48%). The two regioisomers could be separated by reversed phase HPLC.

Synthesis of 2-iodohexadecanol [20] and 2-iodooctanol [38]

2-Iodohexadecanol [20] and 2-iodooctanol [38] were prepared respectively by reduction of 2-iodohexadecanal [1] and 2-iodooctanal [2] by NaBH4 (Scheme 6)5.

 

 

 

 

 

 

 

 

Synthesis of 2-iodohexadecanenitrile [23]

2-Iodohexadecanenitrile [23] was prepared in several steps from pentadecan-1-ol [39]. The latter was first oxidized into n-pentadecanal [40] by PCC (yield 83%)8. Treatment of 40 with TMSCN and ZnI235-38 afforded trimethylsilylcyanohydrin 41, which was deprotected with citric acid into 42 (yield for the two steps: 55%). This compound was also obtained in approximately the same yield by column chromatography of crude 41 on silica gel. These moderate yields can be explained by partial polymerisation of n-pentadecanal [40] under the reaction conditions used for the cyanohydrin formation. Mesylation of cyanohydrin 42 with ClSO2CH3 afforded 2-mesyloxyhexadecanenitrile [43] in a 100% yield30. Finally, 2-iodohexadecanenitrile was obtained in a 57% yield by substitution of the mesyloxy group of 43 by iodide.

The testing of these analogues on the H2O2 production and on the thyroid gland adenylyl cyclase has been performed and the results have been published elsewhere3,4.

 

Experimental

1H-NMR spectra were recorded on a BRUKER WM 250 spectrometer and are reported in ppm from internal TMS on the d scale (CDCl3). Data are reported as follows: chemical shift [multiplicity (s: singlet; bs: broad singlet; d: doublet; bd: broad doublet; t: triplet; m: multiplet; dm: double multiplet), coupling constant in Hertz, integration]. Infrared spectra were taken with Bruker IFS 25 instrument as a film on a NaCl disk unless otherwise stated. EIMS were recorded on a VG Micromass 7070 or Autospec spectrometer. Peak intensities are expressed as % relative to the base peak. Thin layer chromatography analyses were performed on 0.25 mm POLYGRAM silica gel SIL G/UV254 precoated plates (MACHEREY-NAGEL). Column chromatographies were performed over silica gel (MERCK 60 0.04-0.063 mm), using the flash technique. All reactions were run under nitrogen atmosphere. During work-up, organic solutions were dried over MgSO4.

n-Pentadecanal, n-hexadecanal [9], n-octadecanal and n-eicosanal were prepared by PCC oxidation of the corresponding alcohols. As an example, the procedure for the preparation of n-hexadecanal is given here.

n-Hexadecanal [9]. 5.33 g of PCC (24.7 mmol; 1.5 eq.) were suspended in 30 mL of dry CH2Cl2; 4.00 g of hexadecan-1-ol (16.4 mmol; 1.0 eq.) dissolved in 16 mL of dry CH2Cl2 were added at once and the reaction mixture was stirred at rt. for 1.5 h after which 30 mL of dry diethylether was added. The reaction mixture was filtered on a filter paper and the black precipitate washed with dry diethylether (3 x 10 mL). Evaporation of the combined extracts in vacuo and filtration of the residue on Florisil (elution with hexane/diethylether 8:2) afforded 3.21 g of n-hexadecanal (81%) as a white solid after evaporation of the solvent. M.p.: 30-31 °C. IR: 2954, 2923, 2853, 1712, 1728, 1465, 1456 cm-1. EIMS: C16H32O (M = 240); m/z: 240 (M, 0.8), 222 (0.8); 196 (1.6); 44 (23). 1H-NMR: 9.76 (t, 1.9 Hz, 1 H); 2.41 (dt, 1.9 Hz, 7.3 Hz, 2 H); 1.63 (m, 2 H); 1.26 (m, 24 H); 0.88 (m, 3 H).

n-Pentadecanal. M.p.: 55-59 °C. IR: 2956, 2918, 2850, 1704, 1466 cm-1. EIMS: C15H30O (M = 226); m/z = 226 (M, > 0), 225 (50), 183 (58), 182 (83), 44 (100). 1H-NMR: 9.76 (t, 1.9 Hz, 1 H); 2.41 (dd, 7.3 Hz, 1.9 Hz, 2 H); 1.57-1.72 (m, 2 H); 1.26 (m, 22 H), 0.88 (m, 3 H).

n-Octadecanal. M.p.: 41-42 °C. IR: 2953, 2914, 2849 , 2746, 1711, 1470 cm-1. EIMS: C18H36O (M = 268); m/z = 268 (M), 250 (21), 224 (10), 85 (48), 71 (84), 57 (99), 44 (50), 43 (100), 29 (67). 1H-NMR: 9.76 (t, 1.9 Hz, 1 H); 2.41 (td, 7.3 Hz, 1.9 Hz, 2 H); 1.63 (m, 2 H); 1.26 (m, 28 H); 0.88 (m, 3 H).

n-Eicosanal. IR: 2915, 2848, 1711, 1471 cm-1; in CCl4: 2932, 2854; 2714; 1729; 1468 cm-1. EIMS: C20H40O (M = 296); m/z = 296 (M, 1); 278 (2); 252 (3); 44 (18). 1H-NMR: 9.76 (t, 1.9 Hz, 1 H); 2.41 (dt, 7.3 Hz, 1.9 Hz, 2 H); 1.66-1.57 (m, 2 H); 1.26 (m, 32 H); 0.88 (m, 3 H).

2-Iodooctanal [2], 2-iodododecanal [3], 2-iodohexadecanal [1], 2-iodooctadecanal [4], 2-iodoeicosanal [5] were prepared by direct iodination of the corresponding aldehydes using HgCl2/I2. As an example, the procedure for the preparation of 2-iodohexadecanal is given here.

2-Iodohexadecanal [1]. To 250 mg (1.04 mmol) of n-hexadecanal in 2 mL of CH2Cl2 were added 0.141 g (0.520 mmol; 0.5 eq.) of HgCl2 and 264 mg (1.04 mmol; 1 eq.) of iodine. The heterogeneous reaction mixture was stirred vigorously at rt. for 2 h after which the solution was filtered and the filtrate washed successively with an aqueous 0.1 N sodium thiosulfate solution (until discoloration) and an aqueous saturated KI solution. The organic phase was dried, evaporated in vacuo and the resulting residue submitted to flash chromatography on silica gel (hexane/diethylether 8:2) affording 212 mg of 2-iodohexadecanal (56%) as an oil. IR: 2953, 2923, 2852, 2710, 1719, 1466 cm-1. EIMS: C16H31OI (M = 366); m/z 366 (M, 0.4), 239 (19); 221 (12); 170 (14); 43 (100). 1H-NMR: 9.26 (d, 3.2 Hz, 1 H); 4.45 (dt, 7.3 Hz, 3.2 Hz, 1 H), 1.96-1.91 (m, 2 H); 1.26 (m, 24 H); 0.88 (m, 3 H).

2-Iodooctanal [2]. Oil. IR: 2956, 2927, 2857, 2718, 1717, 1466 cm-1. EIMS: C8H15OI (M = 254); m/z = 254 (M, 2); 170 (85); 127 (100); 109 (100); 84 (21). 1H-NMR: 9.26 (d, 3.2 Hz, 1 H); 4.45 (td, 7.3 Hz, 3.2 Hz, 1 H); 2.04-1.84 (m, 2 H); 1.56-1.23 (m, 8 H); 0.88 (m, 3 H).

2-Iodododecanal [3]. Oil. IR: 2954, 2924, 2854, 2722, 1721, 1465 cm-1. EIMS: C12H23OI (M = 310); m/z = 310 (M, 0.8); 183 (100); 170 (100); 165 (69);140 (32). 1H-NMR: 9.26 (d, 3.2 Hz, 1 H); 4.45 (dt, 7.3 Hz, 3.2 Hz, 1 H); 2.00-1.90 (m, 2 H); 1.49-1.26 (m, 16 H); 0.88(m, 3 H).

2-Iodooctadecanal [4]. M.p.: 42-44 °C. IR: 2923, 2853, 2719, 1722, 1464 cm-1. EIMS: C18H35OI ( M = 394); m/z = 394 (M, 1.5), 267 (99), 249 (99), 224 (21), 170 (100), 141 (16), 127 (25), 113 (43), 99 (96), 85 (100), 71 (100), 57 (100), 43 (100), 29 (100). 1H-NMR: 9.25 (d, 3.2 Hz, 1 H); 4.45 (t, 7.3 Hz, 3.2 Hz, 1 H); 1.94 (m, 2 H); 1.26 (m, 28 H); 0.88 (m, 3 H).

2-Iodoeicosanal [5]. IR: 2953, 2918, 2850, 2725, 1716, 1471 cm-1. EIMS: C20H39OI (M = 422); m/z = 422 (M, 5); 421 (10); 295 (100); 277 (100); 252 (52); 170 (100). 1H-NMR: 9.25 (d, 3.2 Hz, 1H); 4.45 (dt, 7.3 Hz, 3.2 Hz, 1 H); 2.00-1.89 (m, 2 H); 1.49-1.26 (m, 32 H); 0.88 (m, 3 H).

2-Bromohexadecanal [6]. A mixture of 336 mg (140 mmol, 1 eq.) of n-hexadecanal, 200 mL (218 mg, 240 mmol, 1.7 eq.) of DMSO and 630 mL t-butyl bromide (766 mg, 560 mmol, 4 eq.) was stirred at 60-65 °C for 6 h. The reaction mixture was poured into water and extracted with diethylether. The organic phase was dried, evaporated in vacuo and the resulting residue was chromatographed on Florisil (toluene/hexane 5:5) to afford 175 mg (0.548 mmol) of 2-bromohexadecanal [6] (41%) as an oil. IR: 2923, 2853, 2714, 1732, 1467, 1456 cm-1. EIMS: C16H31OBr (M = 318); m/z = 318 (M, 4); 239 (9); 221 (19); 124 (41); 57 (100). 1H-NMR: 9.42 (d, 3.2 Hz, 1 H); 4.21 (m, 1 H); 1.2-2.4 (m, 26 H); 1.26 (m, 3 H).

n-Hexadecanal methyl acetal [24]. To 100 mg (0.416 mmol; 1 eq.) of n-hexadecanal and 45.5 L (0.416 mmol; 1 eq.) of methylorthoformate dry methanol (13 mL) were added 8 mg (0.0416 mmol; 0.1 eq.) of p-toluenesulfonic acid. The reaction mixture was stirred at reflux for 2 h after which it was diluted with pentane (10 mL), washed with an aqueous NaOH solution (0.5%; 10 mL) and the aqueous phase extracted with pentane (3 x 10 mL). The combined organic phases were dried, evaporated in vacuo and the resulting residue was flash chromatographed on silica gel (hexane/AcOEt 95:5) to afford 95.9 mg (80%) n-hexadecanal methyl acetal [24] as an oil. IR: 2924, 2854, 1466, 1192, 1124, 1074, 1056 cm-1. EIMS: C18H38O2 (M = 286); m/z = 286 (M, 7), 285 (22), 255 (63), 75 (100). 1H-NMR: 4.35 (t, 5.7 Hz, 1 H); 3.31 (s, 6 H); 1.57 (m, 2 H); 1.25 (m, 26 H); 0.88 (m; 3 H).

2-Chlorohexadecanal methylacetal [25]. 237 mg (0.829 mmol, 1 eq.) of n-hexadecanal methyl acetal and 52.1 mg (0.415 mmol, 0.5 eq.) of MnCl2 were dissolved in an acetonitrile-methanol mixture (0.41mL: 0.41mL). After complete dissolution of MnCl2, 86.4 mg (0.994 mmol; 1.2 eq.) of MnO2 were added. The reaction mixture was stirred at 40 °C and 505 mL (3.98 mmol; 4.8 eq.) of TMSCl were added at once. The reaction mixture became black and was stirred at 40 °C for 19 h after which it was diluted with pentane (20 mL) and washed with an aqueous NaOH solution (1.5%; 2 x 20 mL). The aqueous phase was extracted with pentane (2 x 20 mL). The combined organic phases were dried, evaporated in vacuo and the resulting residue was flash chromatographed on silica gel (hexane/CH2Cl2 7:3) to afford 196 mg of a mixture of 2-chlorohexadecanal methyl acetal [25] (67%) and methyl palmitate (12%). IR: 2924, 2854, 1468, 1190, 1120, 1080, 722 cm-1. EIMS: C18H37O2Cl (M = 320, 322); m/z = 322 (M 37Cl, 0.3), 320 (M+• 35Cl, 0.7 ), 321 (0.7), 319 (2.6), 75 (100). 1H-NMR: 4.31 (d, 5.7 Hz, 1 H); 3.87 (m, 1 H); 3.44 (s, 6 H); 1.65 (m, 4 H); 1.26 (m, 22 H); 0.88 (m, 3 H).

2-Chlorohexadecanal [7]. To 46.0 mg (0.143 mmol) of 2-chlorohexadecanal methyl acetal [25] in 0.5 mL of CH2Cl2 were added 125 mL of trifluoroacetic acid and 125 mL of water. The reaction mixture was stirred at reflux for 4 h after which it was diluted with CH2Cl2 (20 mL) and washed with an aqueous NaHCO3 solution (5%; 3 x 20 mL). The aqueous phase was extracted with CH2Cl2 (3 x 20 mL) and the combined organic phases were dried, evaporated in vacuo and the resulting residue was flash chromatographed on silica gel (hexane/CH2Cl2 7:3) to afford 28 mg (71%) of 2-chlorohexadecanal [7] as a solid. M.p.: 49-50 °C. IR: 2924, 2854, 2714, 1738, 1466, 722 cm-1. EIMS: C16H31OCl (M = 274, 276); m/z = 276 (M 37Cl, 3.6), 274 (M 35Cl, 7.9), 256 (2.1), 239 (1.4), 221 (8.6), 196 (14), 80 (14), 78 (41), 43 (100). 1H-NMR: 9.48 (d, 2.5 Hz, 1 H); 4.15 (ddd, 8.1 Hz, 5.5 Hz, 2.5 Hz, 1 H); 1.88 (m; 2 H); 1.26 (m, 24 H); 0.88 (m, 3 H).

2-Bromopalmitic acid methyl ester [27]. A mixture of 1.00 g (3.90 mmol; 1eq.) of palmitic acid [26] and 121 mg (3.90 mmol; 1eq.) of red phosphorus was heated at 80 °C. After melting of the palmitic acid, 728 mL (14.2 mmol; 3.6 eq.) of bromine was added dropwise over 1 h. The reaction mixture was stirred at 80 °C for 24 h, after which it was cooled at 0 °C (ice bath) and 440 mL of methanol were added dropwise over 1 h. The reaction mixture was stirred at rt. for 30 min. and heated at 80 °C for 1 h. It was diluted under stirring with hexane (25 mL) and with an aqueous NaHSO3 solution (50 mL, 1%). The aqueous phase was extracted with hexane (25 mL) and the combined organic phases were washed with water (4 x 25 mL) until neutral pH. The organic phase was dried, evaporated in vacuo and the resulting residue was flash chromatographed on silica gel (hexane/ CH2Cl2 7:3) to afford 906 mg (67%) of 2-bromopalmitic acid methyl ester as an oil. IR: 2924, 2854, 1748, 1464, 1436, 1272, 1152 cm-1. EIMS: C17H33O2Br (M = 348, 350); m/z = 350 (M+•81Br, 37), 348 (M+•79Br, 36), 319 (2), 317 (1.5), 269 (100), 138 (100), 136 (100), 59 (83). 1H-NMR: 4.22 (t, 7.4 Hz, 1 H); 3.78 (s, 3 H); 2.00 (m, 2 H); 1.26 (m, 24 H); 0.88 (m, 3 H).

2-Fluoropalmitic acid methyl ester [29]. To 107 mg of 2-bromopalmitic acid methyl ester [27] (0.306 mmol; 1 eq.) dissolved in 704 mL of acetonitrile were added 1.8 mL of water and 176 mg (1.38 mmol; 4.5 eq.) of AgF. The reaction mixture was stirred at 80 °C for 48 h after which it was filtered with CH2Cl2 (10 mL) on a short silica gel column. The organic phase was evaporated in vacuo and the resulting residue was flash chromatographed on silica gel (hexane/ CH2Cl2 7:3) to afford 44.3 mg (50%) of 2-fluoropalmitic acid methyl ester [29] as a white solid. M.p.: 34-35 °C. IR: 2954, 2925, 2854, 1770, 1747, 1467, 1440, 1287, 1212 cm-1. EIMS: C17H33O2F (M = 288); m/z: 288 (M, 69), 269 (0.7), 227 (76), 161 (96), 147 (67), 105 (48), 92 (100), 59 (24). 1H-NMR: 4.90 (dt, 48.9 Hz, 6.3 Hz, 1 H); 3.79 (s, 3 H); 1.88 (m, 2 H); 1.26 (m, 24 H); 0.88 (m, 3 H).

2-Fluorohexadecanol. To a suspension of 11.8 mg (0.312 mmol; 3 eq.) of LiAlH4 in 2 mL of dry diethylether under stirring, were added dropwise 30.0 mg (0.104 mmol; 1eq.) of 2-fluoropalmitic acid methyl ester [29] dissolved in 2 mL of dry diethylether. The reaction mixture was refluxed for 4 h, after which it was quenched by addition of ethyl acetate (1 mL) and water (1 mL). The resulting mixture was stirred at rt. for 4 h. Filtration on a short silica gel column (elution with 10 mL of diethylether) and evaporation of the solvent in vacuo afforded 22.6 mg (83%) of 2-fluorohexadecanol as a white solid. M.p.: 58-60 °C. IR: 3269 , 2955, 2916, 2849, 1470, 1072 cm-1. EIMS: C16H33OF (M = 260); m/z = 260 (M, > 0), 196 (24), 113 (26), 99 (44), 85 (100), 71 (100), 57 (100), 43 (100), 31 (85), 29 (100). 1H-NMR: 4.50 (dm, 48.3 Hz, 1 H); 3.77 (dm, 23 Hz, 2 H); 1.87 (t, 6.4 Hz, 1 H); 1.64 (m, 2 H); 1.26 (m, 24 H), 0.88 (m, 3 H).

2-Fluorohexadecanal [8]. 23.0 l (0.251 mmol; 3.3 eq.) of oxalyl chloride were dissolved in 200 mL of dry CH2Cl2 and stirred at –40 °C (dry ice-acetonitrile bath); 39 mL (0.502 mmol; 6.6 eq.) of DMSO were added over 2 min; then, 19.8 mg (0.0760 mmol; 1 eq.) of 2-fluorohexadecanol dissolved in 1 mL of CH2Cl2 were added dropwise over 5 min and the reaction mixture was stirred at –40 °C for 15 min. The reaction mixture was quenched by addition of 159 mL (1.14 mmol; 15 eq.) of triethylamine, stirred 5 min at -40 °C and allowed to warm at rt. It was diluted with CH2Cl2 (10 mL) and washed with water (10 mL). The aqueous phase was extracted with CH2Cl2 (2 x 10 mL). The combined organic phases were dried, evaporated in vacuo to afford 18.0 mg (92%) of 2-fluorohexadecanal as a white solid. M.p.: 58-59 °C. IR: 2916, 2848, 1736, 1468 cm-1. EIMS: C16H31OF (M: 258); m/z = 258 (M, 3), 239 (3), 238 (7), 98 (100), 84 (59), 71 (21), 62 (5), 57 (44), 43 (49), 29 (14). 1H-NMR: 9.76 (dd, 6.2 Hz, 0.73 Hz, 1 H); 4.81 (dm, 48.8 Hz, 1 H); 1.82 (m, 2 H); 1.46 (m, 2 H), 1.26 (m, 22 H), 0.88 (m, 3 H).

1,2-Hexadecanediol [31]. To a solution of 1.00 g (4.46 mmol; 1 eq.) 1-hexadecene [30] in 100 mL of acetone, were added 15.0 mg (0.0579 mmol; 0.013 eq.) of osmium tertroxide and 90.0 mg (6.68 mmol; 1.5 eq.) of N-methylmorpholine monohydrate. The reaction mixture was stirred for 24 h at rt. It was then diluted with an aqueous sodium bisulfite solution (10%, 100 mL) and stirred for 45 min. after which it was washed with 50 mL of brine and the aqueous phase was extracted with CH2Cl2 (4 x 50 mL). The organic extracts were dried and evaporated in vacuo and the resulting residue was flash chromatographed on silica gel (hexane/diethylether 7:3) affording 913 mg of [31] (80%) as a white solid. IR (solution, CHCl3, 0.01 M): 3684, 3626, 3594, 3574, 3038, 3006, 2928, 2856, 1464, 1240, 1194, 1054, 928 cm-1. EIMS: C16H34O2 (M = 258); m/z = 227 (61), 83 (100), 69, 61 (35), 55, 43. 1H-NMR: 3.72 (m, 1 H); 3.66 (dd, 10.8 Hz, 3.0 Hz, 1H); 3.43 (dd, 10.8 Hz, 7.5 Hz, 1H); 1.84 (bs, 2 H); 1.26 (m, 26 H); 0.88 (m, 3H).

1-Tert-butyldimethylsilyloxy-2-hydroxyhexadecane [32]. To a solution of 700 mg (2.71 mmol; 1 eq.) of 1,2-hexadecanediol [31] in 13 mL of CH2Cl2 were added 13.2 mg (0.108 mmol; 0.04 eq.) of DMAP, 450 mg (2.99 mmol; 1.1 eq.) of tert-butyldimethylsilyl chloride and 414 mL (2.99 mmol; 1.1 eq.) of triethylamine. The reaction mixture was stirred for 22 h after which it was diluted with CH2Cl2 (20 mL), washed with water (20 mL) and with a saturated aqueous NH4Cl solution (20 mL). The combined organic phases were dried, concentrated in vacuo and the residue flash chromatographed on silica gel (hexane/diethylether 6:4) to afford 940 mg of 1-tert-butyldimethylsilyloxy-2-hydroxyhexadecane [32] as an oil (93%). IR: 3466, 2954, 2926, 2854, 1464, 1362, 1254, 1112, 1096, 1006, 838, 778 cm-1. EIMS: C22H48O2Si (M = 372); m/z = 341 (M- CH3 - CH3 - H, 5 ), 315 (M- C4H9, 33 ), 297 (21 ), 175 (M- C14H29, 6 ), 147 (11), 131 (29 ), 115 (16 ), 105 (80 ), 75 (100 ). 1H-NMR: 3.61 (m, 1H); 3.61 (dd, 10.5 Hz, 3.2 Hz, 1H); 3.38 (dd, 10.5 Hz, 8.3 Hz, 1H); 2.38 (bs, 1H); 1.25 (m, 28 H); 0.90 (s, 9 H); 0.87 (m, 3H); 0.065 (s, 6 H).

1-Tert-butyldimethylsilyloxy-2-mesyloxyhexadecane [33]. To a solution of 940 mg (2.52 mmol; 1 eq.) of 1-tert-butyldimethylsilyloxy-2-hydroxyhexadecane [32] and 526 mL (3.78 mmol; 1.5 eq.) of triethylamine in 13 mL of dry CH2Cl2 at 0 °C, were added dropwise over 3 min 215 mL (2.78 mmol; 1.1 eq.) of mesylchloride. The reaction mixture was stirred for 10 min at 0 °C, 80 min. at rt. and then, diluted with brine (10 mL). The aqueous phase was extracted with CH2Cl2 (3 x 10 mL) and the combined organic phases were dried, concentrated in vacuo to afford pure 1-tert-butyldimethylsilyloxy-2-mesyloxyhexadecane [33] as an oil (1.02 g, 92%). IR: 2954, 2926, 2856, 1464, 1360, 1254, 1178, 1118, 920, 838, 780 cm-1. EIMS: C23H50O4SiS (M = 450); m/z = 429 (1.8), 355 (3.4), 341 (1.7), 298 (7), 297 (23), 195 (7), 171 (17), 153 (100), 75 (41), 73 (36). 1H-NMR: 4.64 (m, 1 H); 3.74 (d, 2.5 Hz, 1 H); 3.72 (d, 0.9 Hz, 1 H); 3.04 (s, 3 H); 1.65 (m, 2 H); 1.26 (m, 24 H); 0.90 (s, 9 H), 0.88 (m, 3 H), 0.082 (s, 3 H); 0.075 (s, 3 H).

2-Mesyloxyhexadecanol [34]. To a solution of 77.3 mg (0.190 mmol; 1 eq.) of 1-tert-butyldimethylsilyloxy-2-mesyloxyhexadecane [33] in 2 mL of CH2Cl2 were added 0.9 mL trifluoroacetic acid and 0.1 mL of water. The reaction mixture was stirred vigorously for 67 h at rt., and then, diluted with CH2Cl2 (10 mL) and neutralized with an aqueous NaHCO3 solution (10%). The aqueous phase was extracted with CH2Cl2 (3 x 20 mL) and the combined organic phases were dried, concentrated in vacuo and the residue flash chromatographed on silica gel (hexane/diethylether 8:2) to afford 2-mesyloxyhexadecanol [34] as a white solid (49.3 mg, 77%). M.p.: 50-51 °C. IR: 3532, 3034, 2956, 2918, 2852, 1470, 1328, 1164, 1072, 976, 920, 804, 720 cm-1. EIMS: C17H36O4S (M = 336); m/z = 269 (0.7), 240 (2), 241 (4), 227 (37), 194 (12), 180 (6), 43 (100). 1H-NMR: 4.76 (m, 1H); 3.81 (dd, 12.5 Hz, 3.0 Hz, 1 H); 3.71 (dd, 12.5 Hz, 6.8 Hz, 1 H); 3.09 (s, 3H); 1.50-1.74 (m, 2 H); 1.26 (m, 24 H); 0.88 (m, 3 H).

2-Mesyloxyhexadecanal [10]. It was synthesized following the same procedure as that described for the synthesis of 2-fluorohexadecanal (see above). Oil (yield: 58%). IR: 3030, 2920, 2852, 1742, 1468, 1348, 1174, 1072, 1046, 972, 942, 920, 722 cm-1. EIMS: C17H34O4S (M = 334); m/z = 334 (M, 0.24), 305 (0.86), 291 (0.12), 278 (0.18), 209 (7), 138 (14), 55 (100). 1H-NMR: 9.54 (d, 0.7 Hz, 1 H); 4.86 (ddd, 8.0 Hz, 4.7 Hz, 0.7 Hz, 1 H); 3.08 (s, 3 H); 1.66-1.89 (m, 2 H); 1.18 (m, 24 H); 0.80 (m, 3 H).

2-Heptadecanol [35]. To 152 mg (6.24 mmol; 3 eq.) of magnesium (Aldrich) suspended in 7 mL of dry diethylether at rt., were added dropwise 388 mL (6.24 mmol; 3 eq.) of methyl iodide dissolved in 7 mL of dry diethylether over 35 min. To this mixture under stirring, were added dropwise over 15 min 500 mg (2.08 mmol; 1 eq.) of n-hexadecanal dissolved in 7 mL of dry diethylether. After 45 min, the reaction mixture was quenched by addition of water (20 mL) and of an aqueous H2SO4 solution (15%; 4 mL) and diluted with diethylether (10 mL). After washing of the organic phase with water (3 x 15 mL), drying and evaporation in vacuo, the residue was flash chromatographed on silica gel (hexane/diethylether 7:3) to afford 2-heptadecanol [35] as a solid (298 mg, 53%). M.p.: 35-36 °C. IR: 3345, 2956, 2916, 2849, 1467 cm-1. EIMS: C17H36O (M = 256); m/z = 256 (M, 2.2), 255 (14), 241 (27), 238 (73), 210 (37), 99 (30), 85 (100), 71 (100), 57 (100), 43 (100), 29 (64). 1H-NMR: 3.77 (m, 1 H); 1.42 (m, 2 H); 1.26 (m, 26 H); 1.18 (d, 6.1 Hz, 3 H); 0.88 (m, 3 H).

2-Heptadecanone [36]. 53.0 mg (0.246 mmol; 1.5 eq.) of PCC (freshly recrystallised from water) were suspended in 600 mL of dry CH2Cl2; 42.0 mg (0.164 mmol; 1 eq.) of 2-heptadecanol [35] dissolved in 250 mL of dry CH2Cl2 were added at once and the reaction mixture was stirred under reflux for 4 h. The reaction mixture was diluted with 3 mL of dry diethylether, filtered and the black precipitate washed with diethylether. Evaporation of the filtrate in vacuo and filtration of the residue on Florisil (elution with 50 mL diethylether) afforded 38.8 mg of crude 2-heptadecanone which was further flash chromatographed on silica gel (hexane/diethylether 95:5) to afford 26.6 mg (64%) of 2-heptadecanone [36] as a solid and 2.0 mg of the starting alcohol [35] (5%). M.p.: 42-43 °C. IR: 2955, 2916, 2849, 1712, 1472, 1463 cm-1. EIMS: C17H34O (M = 254); m/z = 254 (M, 99), 239 (25), 196 (50), 99 (13), 85 (100), 71 (100), 58 (100), 57 (100), 43 (100), 29 (63). 1H-NMR: 2.41 (t, 7.4 Hz, 2 H); 2.13 (s, 3 H); 1.58 (m, 2 H); 1.26 (m, 24 H); 0.88 (m, 3 H).

3-Iodo-2-heptadecanone [17]. To 42.0 mg (0.165 mmol; 1 eq.) of 2-heptadecanone [36] in solution in 330 mL of CH2Cl2 were added 22.4 mg (0.0826 mmol; 0.5 eq.) of HgCl2 and 41.9 mg (0.165 mmol; 1 eq.) of iodine. The heterogeneous reaction mixture was stirred vigorously at rt. for 2 h after which it was filtered, the solid was washed with 10 mL of CH2Cl2 and the organic extracts washed successively with an aqueous sodium thiosulfate solution (0.1 N; 10 mL) and an aqueous saturated KI solution (10 mL). The organic phase was dried, evaporated in vacuo and the resulting residue flash chromatographed on silica gel (hexane/ CH2Cl2 8:2) affording 33.2 mg of a mixture of 3-iodo-2-heptadecanone [17] (46%) and 1-iodo-2-heptadecanone (7%). The two regioisomers were separated by HPLC (reversed phase LichroCart C18 100mm; elution with CH3CN).M.p.: 33-34 °C. IR: 2953, 2923, 2853, 1713, 1464 cm-1. EIMS: C17H34OI (M = 380); m/z = 380 (M, > 0), 253 (56), 184 (42), 99 (22), 85 (37), 71 (100), 69 (63), 57 (98), 43 (100), 29 (39); 1H-NMR: 4.44 (t, 7.5 Hz, 1 H); 2.41 (s, 3 H); 1.92 (m, 2 H); 1.26 (m, 24 H); 0.88 (m, 3 H).

2-Iodopalmitic acid [18]. 400 mg (1.56 mmol; 1 eq.) of palmitic acid [26], 99.0 mg (0.390 mmol; 0.25 eq.) of iodine and 104 mL (1.56 mmol; 1 eq.) of chlorosulfonic acid were dissolved in 1.60 mL of dry 1,2-dichloroethane. The reaction mixture was heated at 80 °C for 2 h, after which it was diluted with 1,2-dichloroethane (3 mL) and washed successively with water (2 x 5 mL) and an aqueous Na2S2O3 solution (0.1 N) until the color changed from pink to white. The organic phase was dried, evaporated in vacuo and the resulting residue flash chromatographed on silica gel (AcOEt + 0.1% CF3COOH) affording 366 mg of a 75:25 mixture of 2-iodopalmitic acid [18] and palmitic acid [26]. The two products were separated by HPLC [LicroCart, C18 (100 mm), l = 200 nm, CH3CN/water 9:1 + 0.1% CF3COOH, 10 mL/min: tR1 = 8.35 min (palmitic acid), tR2 = 9.29 min (2-iodopalmitic acid)]; 2-iodopalmitic acid [18] was isolated as an oil. IR: 2920, 2850, 1696, 1464, 1416 cm-1. EIMS: C16H31O2I (M = 382); m/z = 382 (M, 1.5 ), 381 (3), 255 (83), 237(46), 57 (100). 1H-NMR: 4.32 (dd, 7.6 Hz, 7.6 Hz, 1 H); 1.97 (m, 2 H); 1.26 (m, 28 H); 0.88 (m, 3 H).

2-Iodooctanoic acid. The same procedure as the one described for the preparation of 2-iodopalmitic acid was used. Thus, 440 mL (2.77 mmol) of octanoic acid afforded after purification of the crude product by flash chromatography (AcOEt to AcOEt/EtOH 5:5 + 0.1% CF3COOH) 248 mg of a 86:14 mixture of 2-iodooctanoic acid and octanoic acid. The two products were separated by HPLC [LicroCart, C18 (100 mm), l = 200 nm, CH3CN/water 7:3 + 0.1% CF3COOH, 10 mL/min: tR1 = 2.40 min (octanoic acid), tR2 = 3.54 min (2-iodooctanoic acid)]; 2-iodooctanoic acid was isolated as an oil. IR: 2956, 2927, 2857, 1713, 1704, 1435, 1417 cm-1. EIMS: C8H15O2I (M = 270); m/z = 270 (M, 9), 143 (27), 125 (56), 28 (100). 1H-NMR: 4.43 (dd, 7.6 Hz, 7.6 Hz, 1 H); 1.97 (m, 2 H); 1.29 (m, 8 H); 0.89 (m, 3 H).

2-Iodopalmitate methyl ester [19]

By iodination of palmitic acid and esterification with methanol. 200 mg (0.780 mmol; 1 eq.) of palmitic acid and 49.0 mg (0.195 mmol; 0.25 eq.) of iodine were dissolved in 780 mL of 1,2-dichloroethane. The reaction mixture was heated at 80 °C and after 2 h 30, 1 mL of methanol (24.7 mmol, 32 eq.) was added. After 3 h, the reaction mixture was cooled, diluted with CH2Cl2 (3 mL) and washed successively with water (2 x 5 mL) and an aqueous Na2S2O3 solution (0.1 N) until the color changed from pink to colorless. The organic phase was dried, evaporated in vacuo and the resulting residue flash chromatographed on silica gel (hexane/ CH2Cl2 7:3) affording 58.3 mg of 2-iodopalmitate methyl ester [19] and 6.8 mg of palmitate methyl ester.

By substitution of the bromine of 2-bromopalmitate methyl ester by iodine. 102 mg (0.291 mmol; 1 eq.) of 2-bromopalmitate methyl ester [27] and 305 mg (2.03 mmol; 7 eq.) of anhydrous NaI were dissolved in 1 mL of acetonitrile at 50 °C. After 20 h, the reaction mixture was diluted with water (10 mL) and CH2Cl2 (10 mL). An aqueous sodium thiosulfate solution (0.1N) was added until discoloration of the aqueous phase. The latter was extracted with CH2Cl2 (3 x 10 mL) and the combined organic phases were dried, evaporated in vacuo affording 108 mg (93%) of 2-iodopalmitate methyl ester [19] as an oil. IR: 2951, 2924, 2853, 1740, 1464, 1435, 1261, 1134 cm-1. EIMS: C17H33O2I (M = 396); m/z = 396 (M, 2), 365 (2), 269 (74), 237 (26), 219 (20), 200 (4.4), 87 (67), 85 (19), 71 (36), 59 (20), 57 (77), 43 (100), 29 (33). 1H-NMR: 4.30 (t, 7.6 Hz, 1 H); 3.75 (s, 3 H); 1.97 (m, 2 H); 1.26 (m, 24 H); 0.88 (m, 3 H).

2-Iodooctanoate methyl ester. The same procedure as the one described for the preparation of 2-iodopalmitate methyl ester was used. Thus, 400 mL (2.77 mmol) of octanoic acid afforded, after purification by flash chromatography (hexane/ CH2Cl2 7:3) 210 mg of 2-iodooctanoate methyl ester and 51.6 mg of octanoate methyl ester as oils. IR: 2954, 2927, 2871, 2857, 1738, 1456, 1435, 1260, 1209, 1170, 1134 cm-1. EIMS: C9H17O2I (M = 284); m/z = 284 (M, 4), 253 (4), 200 (5), 157 (78), 125 (99), 97 (99), 83 (99), 57 (11), 55 (100), 43 (46), 29 (30). 1H-NMR: 4.30 (t, 7.6 Hz, 1 H); 3.75 (s, 3 H); 1.97 (m, 2 H); 1.29 (m, 8 H); 0.88 (m, 3 H).

2-Iodooctanol [38]. To a stirred solution of 40.2 mg (0.158 mmol; 1 eq.) of 2-iodooctanal [3] in 3 mL of methanol kept at rt., were added at once 4.50 mg (0.119 mmol; 0.75 eq.) of NaBH4. After 75 min, the reaction mixture was quenched with water (10 mL), diluted with CH2Cl2 (10 mL) and the organic phase washed with water (3 x 10 mL). The aqueous phase was extracted with CH2Cl2 (2 x 20 mL). The combined organic phases were dried, evaporated in vacuo and the resulting residue flash chromatographed on silica gel (hexane/ CH2Cl2 5:5) affording 19.9 mg (49%) of 2-iodooctanol [38] as an oil. IR: 3354, 2956, 2927, 2870, 2856, 1463 cm-1. EIMS: C8H17OI (M = 256); m/z = 256 (M, 9), 255 (18), 239 (15), 225 (96), 129 (21), 85 (57), 84 (44), 71 (79), 57 (100), 43 (100), 29 (79). 1H-NMR: 4.23 (m, 1 H); 3.73 (m, 2 H); 1.92 (t, 6.6 Hz, 1 H); 1.80 (m, 2 H); 1.29 (m, 8 H); 0.89 (m, 3 H).

2-Iodohexadecanol [20]. The procedure was identical to the one described for the preparation of 2-iodooctanol.

2-Bromohexadecanamide [28]. A solution of 573 mg (1.64 mmol) of 2-bromopalmitate methyl ester [27] in a mixture of methanol/chloroform (17 mL/ 2 mL) was saturated with ammonia at 0 °C in a sealed tube. After 7 h, solvent and ammonia were evaporated and the residue flash chromatographed on silica gel (hexane/ CH2Cl2 7:3) to afford 258 mg (45%) of 2-bromopalmitate methyl ester [27] and 233 mg (42%) of 2-bromohexadecanamide [28] as a solid. M.p: 84-85 °C. IR: 3365, 3185, 2918, 2846, 1662, 1652, 1463 cm-1. EIMS: C16H32ONBr (M = 333, 335); m/z = 335 (M+• 81Br, 6), 333 (M+• 79Br, 6), 254 (100), 139 (90), 137 (90), 98 (28), 83 (20), 72 (80), 69 (30), 59 (41), 55 (42), 43 (54). 1H-NMR: 6.27 (bs, 1 H); 5.59 (bs, 1 H); 4.29 (dd, 8.1 Hz, 5.3 Hz, 1 H); 1.94-2.18 (m, 2 H); 1.26-1.53 (m, 24 H); 0.88 (m, 3 H).

2-Iodohexadecanamide [22]. To a solution of 140 mg (0.420 mmol; 1 eq.) of 2-bromohexadecanamide [28] in 1 mL of acetonitrile were added 441 mg (2.94 mmol; 7 eq.) of anhydrous NaI. The reaction mixture was stirred for 19 h at 80 °C, and then, diluted with water (10 mL) and CH2Cl2 (10 mL). An aqueous sodium thiosulfate solution (0.1 N) was added until discoloration of the aqueous phase, which was extracted with CH2Cl2 (3 x 10 mL) and the combined organic phases were dried, concentrated in vacuo to afford 147 mg (92%) of 2-iodohexadecanamide [22]. M.p.: 105-107 °C. IR: 3366, 3176, 2916, 2870, 1650, 1464, 1426 cm-1. EIMS: C16H32ONI (M = 381); m/z = 381 (M, 2), 254 (100), 185 (11), 83 (18), 72 (70), 69 (26), 59 (74), 55 (38), 43 (56). 1H-NMR: 6.77 (bs, 1 H); 5.40 (bs; 1 H); 4.26 (t, 7.4 Hz, 1 H); 1.94-2.03 (m, 2 H); 1.26-1.53 (m, 24 H); 0.88 (m, 3 H).

2-Hydroxyhexadecanenitrile [42]. To a solution of 700 mg (3.09 mmol; 1 eq.) of n-pentadecanal [40] in 17 mL of CH2Cl2 were added 618 mL (4.64 mmol; 1.5 eq.) of trimethylsilyl cyanide and 3.0 mg (0.00940 mmol; 0.003 eq.) of ZnI. After stirring for 5 h at rt., the 2-trimethylsilyloxyhexadecanenitrile [41] was hydrolyzed by addition of a citric acid solution in methanol (10%; 20 mL) at rt. After 18 h, the reaction mixture was diluted with water (20 mL) and the aqueous phase was extracted with CH2Cl2 (3 x 20 mL). The combined organic phases were washed with brine, dried, concentrated in vacuo and the residue flash chromatographed on silica gel (hexane/ CH2Cl2 9:1 to CH2Cl2, then diethylether) to afford 23.0 mg of starting n-pentadecanal (3%) and 431 mg (55%) of cyanohydrin 42 as a solid. M.p.: 39-40 °C. IR: 3400, 2956, 2920, 2850, 2248, 1468, 1078 cm-1. EIMS: C16H31NO (M = 253); m/z = 253 (M, 5), 208 (15), 182 (16) (100). 1H-NMR: 4.46 (m, 1 H); 2.96 (bd; 5.6 Hz, 1 H); 1.84 (m, 2 H); 1.26 (m, 24 H); 0.88 (m, 3 H).

2-Mesyloxyhexadecanitrile [43]. To a solution of 431 mg (2.55 mmol; 1 eq.) of cyanohydrin [42] and 355 mL (2.55 mmol; 1.5 eq.) of triethylamine in 8.5 mL of dry CH2Cl2 at 0 °C, were added dropwise over 3 min. 145 mL (1.87 mmol; 1.1 eq.) of mesylchloride. The reaction mixture was stirred for 10 min. at 0 °C, 20 min at rt. after which it was diluted with brine (10 mL). The aqueous phase was extracted with CH2Cl2 (3 x 10 mL) and the combined organic phases were dried and concentrated in vacuo to afford 566 mg (100%) of 2-mesyloxyhexadecanitrile [43] as a solid. M.p.: 59-61 °C. IR: 2958, 2916, 2848, 1470, 1368, 1182, 964-818 cm-1. EIMS: C17H33NO3S (M = 253); m/z = 331 (M, > 0), 252 (97), 43 (100). 1H-NMR: 5.17 (dd, 6.7 Hz, 6.7 Hz, 1 H); 3.18 (s, 3 H); 2.00 (m, 2 H); 1.26 (m, 24 H); 0.88 (m, 3 H).

2-Iodohexadecanenitrile [23]. 85.0 mg (0.256 mmol; 1 eq.) of 2-mesyloxyhexadecanenitrile [43] and 270 mg (1.79 mmol; 7 eq.) of anhydrous NaI were dissolved in 2 mL of acetonitrile at 80 °C. After 4 h, the reaction mixture was diluted with water (10 mL) and CH2Cl2 (10 mL). An aqueous sodium thiosulfate solution (0.1 N) was added until discoloration of the aqueous phase which was extracted with CH2Cl2 (3 x 10 mL) and the combined organic phases were dried, concentrated in vacuo and the residue flash chromatographed on silica gel (hexane/ CH2Cl2 9:1) to afford 43.0 mg (57%) of 2-iodohexadecanenitrile [23] as an oil. IR: 2924, 2854, 2236, 1466 cm-1. EIMS: C16H30NI (M = 363); m/z = 363 (M, 2), 236 (100), 192 (55), 128 (47), 124 (39), 110 (51), 97 (83), 43 (81). 1H-NMR: 4.20 (dd, 7.1 Hz, 7.1 Hz, 1 H); 1.96-2.05 (m, 2 H); 1.26 (m, 24 H); 0.88 (m, 3 H).

2-Bromo-2-nonanone [12]. To a solution of 855 mL (5.00 mmol; 1 eq.) of 2-nonanone [15] in 10 mL of acetonitrile, were added dropwise and successively 726 mL (5.50 mmol; 1.1 eq.) of TMSBr and 390 mL (5.50 mmol; 1 eq.) of DMSO. The reaction mixture was stirred for 40 min. at rt. after which it was poured into water (50 mL). The aqueous phase was extracted with diethylether (3 x 20 mL) and the combined organic phases were dried, concentrated in vacuo and the residue flash chromatographed on silica gel (hexane/ CH2Cl2 9:1) to afford 712 mg (64%) of 3-bromo-2-nonanone [12] as an oil. IR: 2958, 2928, 2858, 1720, 1462, 1428, 1358, 1228, 1172, 1148, 724 cm-1. EIMS:C9H17OBr (M = 220, 222; 79Br, 81Br); m/z = 222 (81M, 0.04), 220 (79M, 0.05), 193 (0.02), 191 (0.03), 180 (0.04), 178 (0.04), 151 (0.05), 141 (1), 138 (8), 136 (9), 71 (5), 55 (9), 43 (100), 41 (20), 39 (10). 1H-NMR: 4.22 (dd, 7.9 Hz, 6.7 Hz, 1 H); 2.35 (s, 3 H); 1.96 (m, 2 H); 1.29 (m, 8 H); 0.89 (m, 3 H).

3-Iodo-2-nonanone [11]. 50.5 mg (0.228 mmol; 1eq.) of 3-bromo-2-nonanone [12] and 205 mg (1.37 mmol; 6 eq.) of anhydrous NaI were dissolved in 2 mL of acetonitrile at rt. After 3 h, the reaction mixture was diluted with water (10 mL) and CH2Cl2 (10 mL). The organic phase was washed with water (3 x 10 mL), dried and concentrated in vacuo to afford 47.2 mg (77%) of pure 3-iodo-2-nonanone [11] as an oil. IR: 2956, 2926, 2856, 1712, 1462, 1432, 1358, 1126, 1200, 1166, 1130, 954, 722 cm-1. EIMS:C9H17OI (M = 268); m/z = 184 (0.2), 141 (0.4), 58 (47), 57 (29), 49 (93), 43 (100). 1H-NMR: 4.43 (t, 7.5 Hz, 1 H); 2.41 (s, 3 H); 1.92 (m, 2 H); 1.28 (m, 8 H); 0.88 (m; 3 H).

3-Chloro-2-nonanone [13]. 956 mg (11.0 mmol; 1.1 eq.) of MnO2 were suspended in 20 mL of acetic acid in the presence of 1.71 mL (10.0 mmol; 1 eq.) of 2-nonanone [15]; 5.33 mL (42.0 mmol; 4.2 eq.) of TMSCl were added at once. The reaction mixture was stirred at rt. for 16 h after which it was poured into water (160 mL) and extracted with diethylether (3 x 20 mL). The combined organic extracts were neutralized with an aqueous NaOH solution (0.025 M; 2 x 80 mL), dried, concentrated in vacuo and the residue flash chromatographed on silica gel (hexane/ CH2Cl2 9: 1) to afford 162 mg (92%) of 3-chloro-2-nonanone [13] as an oil. IR: 2958, 2930, 2860, 1724, 1464, 1430, 1358, 1232, 1162, 1116 cm-1. EIMS: C9H17OCl (M = 176, 178; 35Cl, 37Cl); m/z = 178 (37M, 0.15 ), 176 (35M, 0.5), 147 (0.4), 141 (0.1), 94 (9), 92 (24), 86 (31), 84 (42), 58 (20), 51 (25), 49 (50), 43 (100). 1H-NMR: 4.17 (dd, 8.3 Hz, 5.8 Hz, 1 H); 2.31 (s, 3 H); 1.75-2.00 (m, 2 H); 1.29 (m, 8 H), 0.89 (m, 3 H).

3-Fluoro-2-nonanone [14]. To a solution of 122 mg (0.550 mmol; 1 eq.) of 3-bromo-2-nonanone [12] in 2.75 mL of acetonitrile were added 1.4 mL of water (0.1% in weight of AgF) and 140 mg (1.10 mmol; 2 eq.) of AgF. The reaction mixture was stirred at 80 °C for 24 h after which it was filtered on a short column of silica gel (elution with 20 mL CH2Cl2). The filtrate was concentrated in vacuo and the residue flash chromatographed on silica gel (hexane/ CH2Cl2 9:1). Evaporation of the solvent under nitrogen afforded 3-fluoro-2-nonanone [14] as an oil. IR: 2956, 2930, 2860, 1728, 1464, 1424, 1358, 1170, 1122, 1078 cm-1. EIMS: C9H17OF (M = 160); m/z = 160 (M, 0.06), 72 (25), 76 (0.5), 43 (100). 1H-NMR: 4.71 (dm, 50.6 Hz, 1 H); 2.24 (d, 4.7 Hz, 3 H); 1.69-1.89 (m, 2 H); 1.29 (m, 8 H); 0.88 (m, 3 H).

3-Tosyloxy-2-nonanone [16] and 1-tosyloxy-2-nonanone. To 600 mL (3.52 mmol; 1 eq.) of 2-nonanone in 18 mL of dry acetonitrile was added 1.44 g (3.52 mmol; 1 eq.) of HTIB. The reaction mixture was refluxed for 10 min after which the solvent was evaporated in vacuo. The crude residue was dissolved in pentane (20 mL) and the solution washed with water (2 x 10 mL), dried and evaporated in vacuo. The residue was flash chromatographed on silica gel (hexane/diethylether 8:2) to afford 333 mg of 3-tosyloxy-2-nonanone [16] (30%) and 162 mg of 1-tosyloxy-2-nonanone (15%) (67:33) as oils.

3-Tosyloxy-2-nonanone [16]. IR: 2956, 2930, 2860, 1724, 1598, 1462, 1368, 1178, 1096, 952, 888, 832, 816, 772, 668, 556 cm-1. EIMS: C16H24O4 S (M = 312); m/z = 313 (M+ H, 0.5 ), 281 (1), 269 (21), 155 (100), 97 (25), 91 (100), 65 (22), 57 (14), 43 (42). 1H-NMR: 7.80 (AA’XX’ system, 2 H); 7.36 (AA’XX’ system, 2 H); 4.59 (dd, 7.9 Hz, 4.9 Hz, 1 H); 2.46 (s, 3 H); 2.20 (s, 3 H); 1.61-1.70 (m, 2 H); 1.15 (m, 8 H); 0.84 (m, 3 H).

1-Tosyloxy-2-nonanone. IR: 2954, 2928, 2858, 1740, 1598, 1460, 1368, 1178, 1096, 1004, 818, 774, 668, 556 cm-1. EIMS: C16H24O4S (M = 312); m/z = 312 (M, 0.4), 282 (4), 228 (5), 127 (100), 91 (50), 65 (20), 57 (75), 43 (35). 1H-NMR: 7.82 (AA’XX’ system, 2 H); 7.36 (AA’XX’ system, 2 H); 4.49 (s, 2 H); 2.48 (t; 7.3 Hz, 2 H); 2.46 (s, 3 H); 1.52 (m, 2 H); 1.25 (m, 8 H); 0.88 (m, 3 H).

 

Acknowledgements

One of us (H. V.d.B.) gratefully acknowledges the "Institut pour l’Encouragement de la Recherche Scientifique dans l’Industrie et l’Agriculture", the "Fonds pour la formation à la Recherche dans l’Industrie et dans l’Agriculture" and the "Fondation Van Buuren" for financial support. We thank Dr R. Ottinger for the NMR spectra and Dr M. Kaisin and Mr. C. Moulard for the mass spectra.

 

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Received: June 16, 1998