Modular Approach to the Synthesis of Unsaturated 1-Monoacyl Glycerols

Abstract

A modular synthesis of unsaturated 1-monoacylglycerols (1) from cis-1-iodo-1-alkenes [cis-RCH=CHI] and unsaturated carboxylic acids [CH₂=CH(CH₂)_nCO₂H] is described. The method revolves around a Suzuki coupling to establish olefin geometry.

Key Words

Suzuki coupling - 1-monoacylglycerol - protein crystallization - diimide reduction - vinyl iodide

References

• 1 Caffrey M. Structural Biology  2000,  10:  486 
• 2 Jensen RG. Pitas RE. Adv. Lipid. Res.  1977,  14:  213 
• 4 For example, in our hands, alkyne hydrogenation strategies provided cis fatty acids with 2-10% contamination from the corresponding trans fatty acids. In one case we examined differences in oxidation state of the carboxyl terminus at the stage of hydrogenation and catalyst type but were unable to routinely obtain the olefin homogeneities of greater than 99% desired for protein crystallization studies. See: Valicenti AM. Pusch FM. Holman RT. Lipids  1985,  20:  234 
• 5 Miyaura N. Ishiyama T. Sasaki H. Ishikawa M. Satoh M. Suzuki A. J. Am. Chem. Soc.  1989,  111:  314 
• 6 Dieck HA. Heck RF. J. Org. Chem.  1975,  40:  1083 
• 7 For a review of the Suzuki coupling using alkylboranes see: Trauner D. Chemler SR. Danishefsky SJ. Angew. Chem. Int. Ed.  2001,  40:  4544 
• 8 For the conditions and additives used in this study see: Trost BM. Lee CB. J. Am. Chem. Soc.  1998,  120:  6818 

3

In this paper we will refer to 1-MAGs in [N.T] space where N = neck length and T = tail length. For example the 1-MAG in which the fatty acid component is oleic acid will be called [9.9].

9

Representative procedures for the preparation of [12.6] from 4 and 6 follow (entry 8 in Table [1] ).
Preparation of [12.6] Acetonide.
To a solution of 7.94 g (26.7 mmol) of the appropriate ester 4 in 150 mL of THF in a 250 mL round-bottomed flask cooled in an ice-salt bath was added 53.0 mL (26.5 mmol) of 0.5 M 9-BBN in THF over a 12 min period. The cold bath was removed and the solution was stirred for 2 h. To the mixture was added 10 mL of H₂O and the solution was stirred for 15 min. Concurrent with the hydroboration of 4, 1.95 g (2.7 mmol) of Pd(dppf)Cl₂, 8.16 g (26.7 mmol) of triphenylarsine, and 10.55 g (26.7 mmol) of Cs₂CO₃ were sequentially added at 2 min intervals to a solution of 6.0 g (26.7 mmol) of the appropriate vinyl iodide 6 in 100 mL of DMF in a separate flask. The mixture was stirred at r.t. for 2 h followed by addition of the hydroboration mixture via cannula. The resulting dark brown mixture was stirred at r.t. for 4 h followed by addition of 300 mL of brine. The resulting mixture was extracted with three 150 mL portions of Et₂O. The combined organic extracts were dried over Na₂SO₄ and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography over 320 g of silica gel (column diameter = 13 cm) using 1-10% EtOAc in hexane as the eluant. Appropriate fractions were pooled and concentrated and the chromatographic procedure was repeated two times to provide 5.6 g (53%) of the desired [12.6] acetonide as a pale yellow oil. IR (neat): 1742 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 0.85 (t, J = 7 Hz, 3 H), 1.20-1.40 (m with two s at δ = 1.35 and 1.40 ppm, 26 H), 1.60 (quintet, 2 H), 2.00 (m, 4 H), 2.30 (t, J = 7 Hz, 2 H), 3.65 (m, 1 H), 4.00-4.15 (m, 3 H), 4.25 (m, 1 H), 5.30 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 14.00, 22.50, 24.80, 25.20, 26.60, 27.07, 27.09, 29.00, 29.15, 29.18, 29.35, 29.42, 29.46, 29.66, 31.40, 34.00, 64.40, 66.30, 73.60, 109.70, 129.74, 129.79, 173.40. MS (electrospray): m/z calcd for C₂₄H₄₄O₄Na: 419.3132; found: 419.3109.
Preparation of [12.6].
To a solution of 5.6 g (14.2 mmol) of the acetonide in 250 mL of MeOH cooled to 0 °C in an ice-salt bath was added dropwise 12 mL of 1.0 M aq HCl over a 7 min period. The ice bath was removed and the reaction was allowed to warm to r.t. The reaction was stirred for 7 h while the reaction progress was monitored by TLC [silica gel; EtOAc-hexane (15:85)]. To the reaction mixture was added 100 mL of sat. aq NaHCO₃ and the mixture was extracted with four 150 mL portions of CH₂Cl₂. The combined extracts were dried over MgSO₄ and concentrated in vacuo. The crude product (5.2 g) was chromatographed over 200 g of silica gel using 5% EtOAc in hexane as the initial eluant and gradually increasing the EtOAc concentration to 75%. The resulting mixture of 1-MAG and 2-MAG (4.2 g; 95:5, respectively by ¹H NMR) was dissolved in 100 mL of Et₂O-petroleum ether (bp 35-60 °C) was cooled to -20 °C. The resulting crystals were harvested and rinsed with 20 mL of cold Et₂O-petroleum ether to provide 3.4 g (64%; 2 crops) of [12.6] 1-MAG that contained maybe a trace of the 2-MAG by ¹H NMR; mp 53-54 °C. IR (neat): 3250 cm^-1. ¹H NMR (400 MHz, C₆D₆): δ = 0.90 (t, J = 7 Hz, 3 H, 1.20-1.50 (m, 20 H), 1.60 (quintet, 2 H), 2.10 (m, 4 H), 2.20 (t, J = 7 Hz, 2 H), 3.35 (br s, 1 H, OH), 3.55 (m, 1 H), 3.60 (m, 1 H), 3.70 (br s, 1 H, OH), 3.85 (m, 1 H), 4.15 (m, 2 H), 5.45 (m, 2 H). ¹³C NMR (100 MHz, C₆D₆): δ = 14.30, 22.90, 25.20, 27.60, 21.70, 29.51, 29.72, 29.75, 29.86, 29.93, 30.00, 30.04, 30.24, 31.80, 34.30, 63.70, 65.40, 70.70, 130.50, 130.60, 174.30. MS(electrospray): m/z calcd for C₂₁H₄₀O₄Na: 379.2819; found: 379.2845.

10

Whereas the ¹H NMR spectra of acetonide 7 [cis-7.9] and the corresponding trans isomer were indistinguishable, 1% of the trans isomer could be detected in the cis isomer by ¹³C NMR spectroscopy. For example the olefinic carbons in the cis isomer appeared at δ = 130.0 and 130.5 ppm whereas the olefinic carbons in the trans isomer appeared at δ = 131.0 and 131.5 ppm.

11

The olefinic carbons for monoolein [cis-9.9] appeared at δ = 130.1 and 130.4 ppm in C₆D₆ whereas the olefinic carbons for monoelaidin [trans-9.9] appeared at δ = 130.6 and 130.9 ppm in C₆D₆. Other subtle differences between these 1-MAG isomers were detected in the upfield region of their ¹³C NMR spectra.

12

The 2-MAGs gave ¹H NMR signature signals at approximately δ = 4.8 ppm (1 H quintet for secondary OCH) and δ = 3.5 ppm (4 H signal for CH₂OH). The 2-MAGs gave ¹³C NMR signature signals at approximately δ = 62 ppm (OCH₂) and δ = 75 ppm (OCH).