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

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 iodolipid. It is formed upon addition of iodine to the vinyl diethylether group of plasmalogens followed by hydrolysis. The investigation of the biological activities of synthetic (±)-1 revealed its ability to inhibit both H2O2 production in cultured dog thyroid cells and the human thyroid adenylyl cyclase. (2S)-1 and (2R)-1 exhibit identical biological activities, thus suggesting the lack of stereoselectivity in their interaction with the biological receptors. 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.


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 iodolipid 1 .It is formed upon addition of iodine to the vinyl diethylether group of plasmalogens followed by hydrolysis 1,2 .The investigation of the biological activities of synthetic (±)-1 revealed its ability to inhibit both H 2 O 2 production in cultured dog thyroid cells 3 and the human thyroid adenylyl cyclase 4 .(2S)-1 and (2R)-1 exhibit identical biological activities, thus suggesting the lack of stereoselectivity in their interaction with the biological receptors 5 .
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.
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% yield 8 .

Synthesis of 2-mesyloxyhexadecanal [10]
The preparation of 2-mesyloxy-23 and 2-tosyloxyketones 24 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 HTIB 25 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-dioxydedithioketal 26 or the dimethylketal of 2-mesyloxyhexadecanal 27 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 OsO 4 28 followed by selective protection of the primary hydroxyl group of 31 with TBDMSCl 29 , mesylation of the secondary hydroxyl group of 32 with MsCl 30 and deprotection of the primary hydroxyl group of 33 with TFA 31 led to 2-mesyloxyhexadecanol [34].Swern oxidation 20 of 34 gave 2-mesyloxyhexadecanal [10] which proved to be a relatively unstable compound.
3-Iodo-2-nonanone [11] was cleanly synthesized in a 77% yield by substitution of the bromine of 12 by NaI in CH 3 CN.In contrast with literature claims 6 , direct iodination of 2-nonanone [15] with HgCl 2 and I 2 was not regioselective and gave a mixture of 3-iodo-2-nonanone [11] and 1-iodo-2-nonanone (82:18), which have the same R f 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)..Another chlorinating system, TMSCl/DMSO in acetonitrile, is described for the introduction of a chlorine atom into the more substituted position of a ketone 34 ..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 H 2 O 2 production and on the thyroid gland adenylyl cyclase has been performed and the results have been published elsewhere 3,4 .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/UV 254 precoated plates (MACHEREY-NAGEL).Column chromatographies were performed over silica gel (MERCK 60 0.04-0.063mm), using the flash technique.All reactions were run under nitrogen atmosphere.During work-up, organic solutions were dried over MgSO 4 .
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 CH 2 Cl 2 ; 4.00 g of hexadecan-1-ol (16.4 mmol; 1.0 eq.) dissolved in 16 mL of dry CH 2 Cl 2 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. :   [5] were prepared by direct iodination of the corresponding aldehydes using HgCl 2 /I 2 .As an example, the procedure for the preparation of 2-iodohexadecanal is given here.

By substitution of the bromine of 2-bromopalmitate methyl ester by iodine. 102
The same procedure as the one described for the preparation of 2-iodopalmitate methyl ester was used.Thus, 400 µL (2.77 mmol) of octanoic acid afforded, after purification by flash chromatography (hexane/ CH 2 Cl 2 7:3) 210 mg of 2-iodooctanoate methyl ester and 51.6 mg of octanoate methyl ester as oils. in 3 mL of methanol kept at rt., were added at once 4.50 mg (0.119 mmol; 0.75 eq.) of NaBH 4 .After 75 min, the reaction mixture was quenched with water (10 mL), diluted with CH 2 Cl 2 (10 mL) and the organic phase washed with water (3 x 10 mL).The aqueous phase was extracted with CH 2 Cl 2 (2 x 20 mL).The combined organic phases were dried, evaporated in vacuo and the resulting residue flash chromatographed on silica gel (hexane/ CH 2 Cl 2 5:5) affording 19.