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DOI: 10.1002/ejoc.201101472

The Synthesis of Long-Chain -Alkyl--Hydroxy Esters Using Allylic Halides in a FrterSeebach Alkylation
Ashna A. Khan,[a,b] Stephanie H. Chee,[a,b] Bridget L. Stocker,*[b] and Mattie S. M. Timmer*[a]
Keywords: Alkylation / Synthetic methods / Diastereoselectivity / Allylic compounds / Lipids
The FrterSeebach alkylation is a highly efficient means to diastereoselectively introduce -substituents to chiral -hydroxy esters, however, the yields of reactions in which longer chain alkyl halides are used can be disappointing. To provide a more robust protocol for the alkylation of -hydroxy esters, we prepared a variety of long-chain allylic iodides with the view that the greater reactivity of the allylic system would lead to enhanced efficiency. Indeed, for all substrates studied, the yield of the -alkylation was greatly improved for the unsaturated allylic halides compared to their analogous saturated counterparts. Our methodology thus provides an improved means by which to access a variety of important lipophilic compounds such as mycolic acids, which are found on the cell wall of M. tuberculosis.

Introduction
The FrterSeebach alkylation provides a convenient entry to -alkylated -hydroxy esters and is a crucial step in the preparation of a variety of biologically important compounds, which include natural products[13] and derivatives thereof,[47] enzyme inhibitors[8,9] and other key chiral building blocks.[10,11] In Frters early studies, ethyl (S)-3hydroxybutyrate was alkylated with methyl, allyl, butyl and benzyl bromide to give the corresponding (2S,3S)-alkylated products in good yield and excellent diastereoselectivity,[12,13] and the methodology was also used for the alkylation of ethyl (R)-3-hydroxyvalerate using propyl iodide as the electrophile.[14] At approximately the same time, Seebach also performed pioneering studies in this field, illustrated by the alkylation of malic acid diesters with methyl, allyl and benzyl halides.[15] Despite the versatility of the FrterSeebach alkylation in organic synthesis and its potential for the highly diastereoselective introduction of -substitutents to chiral hydroxy esters, the extension of this methodology for longer chain alkyl halides has been met with mixed success.[1618] During the synthesis of the highly immunomodulatory mycolic acids found on the cell wall of M. tuberculosis and other related mycobacteria (e.g. 1; Figure 1),[19,20] Baird and coworkers observed that -alkylations using tetra[a] School of Chemical and Physical Sciences, Victoria University of Wellington, P. O. Box 600, Wellington, New Zealand Fax: +644-463-5237 E-mail: mattie.timmer@vuw.ac.nz bstocker@malaghan.org.nz [b] Malaghan Institute of Medical Research, P. O. Box 7060, Wellington, New Zealand Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/ejoc.201101472.
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cosanyl iodide by the FrterSeebach reaction gave only modest yields (31 %) of the corresponding -alkylated hydroxy esters.[16,17] The group later developed a chainelongation strategy (involving an -alkylation using allyl iodide followed by ozonolysis and Wittig reactions) in subsequent mycolic acid syntheses.[2123] Similarly, Nishizawa et al. had no success when performing a FrterSeebach alkylation using eicosanyl iodide on a tetracosanoyl -hydroxy functionalised ester, however, they observed that a change of ester substrate resulted in product formation.[18] Our own attempts at an -alkylation using eicosanyl iodide gave a disappointing 5 % yield. This illustrates the substrate-specificity and fickleness of the methodology when using lipophilic electrophiles.

Figure 1. Representative mycolic acids.

Given the variable success of the FrterSeebach methodology when using long-chain alkyl halides, we considered
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developing a strategy whereby allyl halides are used as electrophiles. Allyl halides have excellent reactivity, which arises from stereoelectronic interactions between the *CX orbital and the adjacent system.[2426] In the transition state for the SN2 reaction of an allylic halide, the overlap between the p orbital on the carbon atom at which displacement occurs and the p orbitals of the conjugated double bond allows the electron density of the system to be delocalised over the three carbon atoms involved in the allylic system. This, in turn, leads to a lower transition state energy when compared to the transition state of a corresponding saturated halide. Accordingly, we proposed that a FrterSeebach alkylation using highly reactive long-chain allylic iodides would lead to more efficient -alkylations. Our studies to support this hypothesis are presented herein.

A. A. Khan, S. H. Chee, B. L. Stocker, M. S. M. Timmer

of l-malic acid,[31] was alkylated with allylic halides and their saturated counterparts (Table 1). The saturated alkyl iodides were prepared by the iodination of the corresponding alcohols or, in the case of iodotetradecane, by the crosshalogenation of bromotetradecane. The overall yields were, in general, similar to those for the preparation of the allylic iodides. In general, the alkylations were performed in THF using 2.5 equiv. of LDA (generated in situ at 78 C), to which was added 1 equiv. of 5 followed by 1.5 equiv. of the alkylhalide.
Table 1. The FrterSeebach alkylation using a variety of alkyl halides.

Results and Discussion

To prepare the required allylic iodides, we adopted an efficient two-step strategy that first involved the Grignard addition of vinylmagnesium bromide to an aldehyde[24] and a subsequent SN2 substitution of the in situ-generated alkoxytriphenylphosphonium iodide intermediate[27] (Scheme 1). The starting aldehydes, pentanal (2a) and dodecanal (2b), were sourced commercially, whereas octadecanal (2c), eicosanal (2d) and docosanal (2e) were prepared by a PCC oxidation of the corresponding alcohols.[28] For all aldehydes, the Grignard addition proceeded smoothly to give the corresponding allylic alcohols 3ae, though it should be noted that in the case of the longer lipids (n = 16, 18, 20), better yields were obtained when vinylmagnesium bromide was prepared in situ[29] and the reaction performed at 0 C in toluene.[30] The intermediate allylic alcohols 3a e were subjected to filtration through a short silica gel plug and immediately used. Although the alcohols can be purified by flash column chromatography, they are prone to decomposition[27] and storage is not recommended. Treatment of each alcohol with a solution of PPh3 and I2 in THF gave the corresponding allylic iodides 4a (n = 3), 4b (n = 10), 4c (n = 16), 4d (n = 18) and 4e (n = 20) in 89, 81, 70, 71 and 73 % yield, respectively, over two steps. Each of the allylic iodides 4ae were formed as an inseparable isomeric mixture that consisted mainly of the E isomer (E/Z ca. 4:1), as determined by the 18.6 vs. 8.5 Hz coupling constant for the alkene protons in the 1H NMR spectra of the crude reaction mixtures. A very minor amount (5 %) of the corresponding 1,3-diene elimination product was also observed.

[a] Conditions A: LDA (2.5 equiv.), 5 (1 equiv.), RX (1.5 equiv.), THF; conditions B: reaction performed with the addition of HMPA (HMPA/THF 1:1). [b] Isolated yield following purification by flash chromatography. [c] Determined by 1H NMR spectroscopic analysis (in case of the allylic compounds after hydrogenation) of the crude reaction mixture.

Scheme 1. Synthesis of allylic iodides.

With the necessary allylic halides in hand, we investigated their potential in FrterSeebach alkylation. Diethyl (S)-malate (5), prepared in 95 % yield by the esterification
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Our first study involved the alkylation of 5 using either allyl bromide (Table 1, Entry 1) or allyl iodide (Table 1, Entry 2) in the absence of hexamethylphosphoramide (HMPA). Both reactions proceeded smoothly to give anti6a as the predominant diastereomer in respectable yield. Increasing the chain length to C7, however, resulted in 6b in a decreased (37 %) yield following purification by flash column chromatography (Table 1, Entry 3). There was no other identifiable product obtained from the reaction, and
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Synthesis of Long Chain -Alkyl--Hydroxy-Esters Using Allylic Halides

although excess alkyl halide was recovered from the reaction mixture, 5 decomposed. The use of the C7 allylic iodide, 1-iodohept-2-ene (4a), however, resulted in an improved 55 % yield of the desired -alkylated -hydroxy ester with an anti/syn diastereoselectivity of 9:1 (Table 1, Entry 4). This result was encouraging and demonstrated the improved reactivity of the allylic system. The FrterSeebach alkylation was then attempted using the C14 homologous (Table 1, Entries 59). When 1-iodotetradecane was used as the electrophile, a very poor yield of the corresponding -alkylated ester 6d was observed (Table 1, Entry 5). A change to 1-bromotetradecane fared no better, and 6d was formed in decreased yield (7 %; Table 1, Entry 6). In an attempt to improve these yields, HMPA was added to the reaction as a cosolvent. HMPA has been shown to enhance SN2 reactions by its ability to strongly solvate cations[32] and has been used by Utaka et al.[33] and Fujisawa et al.[34] to perform -alkylations using 1-iodotetradecane. Indeed, we observed an improvement in yield (35 %) when HMPA was added (Table 1, Entry 7). These results were compared to similar reactions using the corresponding C14 allylic iodide. In the absence of HMPA, the use of 1-iodotetradec-2-ene (Table 1, Entry 8) gave an improved 51 % yield of 6e (cf. Table 1, Entry 5). Surprisingly, the addition of HMPA to the reaction mixture (Table 1, Entry 9) did not further improve the yield (cf. Table 1, Entry 8). In view of the toxicity of this reagent and the lack of improvement in reaction yield, HMPA was not used in subsequent allylic alkylations. The difficulties to obtain good yields when using longchain alkyl iodides in the FrterSeebach alkylation was further demonstrated when attempts were made to alkylate 5 using 1-iodoeicosane (Table 1, Entry 10). In our hands, this reaction resulted in a dismal 5 % yield. The general problem we encountered when performing this -alkylation was that the reaction was very slow and required the gradual warming of the reaction mixture from 78 to 0 C for any product formation to be observed by TLC. Unfortunately, the temperature at which the reaction commenced (ca. 20 C) was also the temperature at which 5 began to decompose. Many changes to the solvent, reaction time and equivalents of reagents were then made in an attempt to improve this yield without success. A change to iodoeicos2-ene, however, gave the desired -alkylated esters 6g in 49 % yield (Table 1, Entry 11). Although some decomposition of 5 was observed, we were satisfied with the final yield of anti-6g given the difficulty of this -alkylation. Attempts to perform the FrterSeebach alkylation using 1-iododocosane gave a mere 8 % yield of 6h (Table 1, Entry 12), whereas the use of iododocos-2-ene as an electrophile improved the yield to 42 % (Table 1, Entry 13). The methodology was then used to synthesise anti-6j, which contains the most common mycolic acid side chain. Gratifyingly, the yield for this reaction was a respectable 41 % (Table 1, Entry 14). This result was particularly pertinent given that the synthesis of the corresponding linear C24 alkyl iodide takes three steps, which commences with bromododecanol.[16] In all examples, the diastereoselectivity of the allylic alkylEur. J. Org. Chem. 2012, 9951002

ations was excellent (ca. 9:1, anti/syn) and was higher than those observed for the corresponding saturated alkyl halides. Having demonstrated the benefit of allylic halides in the FrterSeebach alkylation, we hydrogenated the ,-unsaturated esters. The mixtures of diastereomers 6 (n = 3, 10, 16, 18, 20) were thus hydrogenated in the presence of catalytic Pd (5 wt.-%, Scheme 2). Following hydrogenation, the diastereomers were separated by flash column chromatography and the desired esters anti-6b (n = 3), anti-6d (n = 10), anti-6f (n = 16), anti-6h (n = 18) and anti-6k (n = 20) were isolated as pure compounds in excellent yields (90 91 %). The excellent yields for the hydrogenation in combination with the significantly improved yields for the allylic alkylation reaction thus demonstrate the potential of our reaction methodology for the synthesis of long-chain -alkylated -hydroxy esters. The esters, in turn, are valuable intermediates en route to the synthesis of the immunomodulatory mycolic acids and derivatives thereof.[1723,35] For example, diester 6b was selectively reduced by treatment with BH3DMS[36] to give diol 7, a versatile building block for the synthesis of lipophilic hydroxy acids.[37]

Scheme 2. Hydrogenation of the unsaturated diesters.

Finally, to confirm that the allylic alkylations give the same major diastereomer as that observed when using saturated alkyl halides, a Grubbs cross-metathesis reaction[38] was performed between anti-6a (of known 2S,3R stereochemistry)[39] and 1-tridecene to give the saturated ester anti-6e in 41 % yield and an E/Z ratio of 4:1 (Scheme 3). In addition, the homodimerisation product of 1-tridecene was observed along with unreacted allylic ester anti-6a, which accounted for the remainder of the material. Hydrogenation of anti-6e then gave a product that exhibited spectroscopic data consistent with those obtained from the direct alkylation of 5 with 1-iodotetradecane (Table 1). This unequivocally established that the major isomer from the allylic alkylation was the anticipated 2S,3R-ester.

Scheme 3. Confirming the stereochemistry of the alkylation products.

To explain the preferential formation of the 2S,3R diastereomer, the rigid cyclic intermediate that is formed during the course of the reaction needs to be considered (Scheme 4). During the alkylation, more than two equivalents of LDA are added to the -hydroxy ester. One equivawww.eurjoc.org

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lent is used to deprotonate the hydroxy group, which results in the formation of a monoanion where the negatively charged oxygen is countered by the lithium cation, and the second equivalent of LDA leads to the formation of an ester enolate in which the lithium cation bridges the two negative charges via a six-membered cyclic intermediate. Regeneration of the carbonyl group then allows the enolate to attack the alkyl halide, RX, at the face opposite to the ester, which is adjacent to the -hydroxy substituent due to steric hindrance.[15] It also should be noted that greater reactivity of the allylic system leads to higher diastereoselectivity due to the ability of the reactions to be performed at lower temperatures.

A. A. Khan, S. H. Chee, B. L. Stocker, M. S. M. Timmer (Pancreac), NaHCO3 (Pure Science), K2CO3 (Pure Science), Na2S2O3 (Pancreac), MgSO4 (Pure Science) and NaCl (Pancreac) were used as received. 1-Iodotetradecane[40] and l-diethyl malate[31] were prepared using literature procedures. Solvents were removed by evaporation at reduced pressure. Reactions were monitored by TLC with MachereyNagel silica gel-coated plastic sheets (0.20 mm, Polygram SIL G/UV254) by coating with a solution of 5 % KMnO4 and 1 % NaIO4 in H2O followed by heating. Column chromatography was performed using Pure Science silica gel (40 63 m). HRMS were recorded with a Waters Q-TOF Premier Tandem Mass Spectrometer using positive electrospray ionisation. Optical rotations were recorded with a PerkinElmer 241 polarimeter or Autopol II instrument (Rudolph Research Analytical) at 589 nm (sodium D-line). IR were recorded as thin films with a Bruker Tensor 27 FTIR spectrometer equipped with an attenuated total reflectance (ATR) sampling accessory. NMR spectra were recorded at 20 C in CDCl3 with a Varian INOVA spectrometer operating at 500 MHz. Chemical shifts are given in ppm () relative to TMS. NMR peak assignments were made using COSY, heteronuclear single quantum coherence and HMBC 2D experiments. General Procedure for the Synthesis of Allylic Iodides: To a solution of aldehyde (10 mmol, 1.0 equiv.) in dry THF (50 mL) was added vinylmagnesium bromide (1 m in THF, 15 mmol, 1.5 equiv.) dropwise at 0 C. For longer lipids 4ce, freshly prepared vinylmagnesium bromide was used and the aldehyde was dissolved in toluene instead of THF. The mixture was stirred for 90 min at 0 C and 1 h at room temperature. The reaction was quenched by the addition of NH4Cl, extracted into Et2O (3 50 mL), and the combined organic layers were dried with MgSO4, filtered, and concentrated in vacuo to give the allylic alcohol as a viscous oil, which was used without further purification. To a solution of PPh3 (15 mmol, 1.5 equiv.) in CH2Cl2 (15 mL) was added iodine (15 mmol, 1.5 equiv.), and the mixture stirred at room temperature for 5 min. A solution of the crude allylic alcohol (10 mmol, 1 equiv.) in CH2Cl2 (30 mL) was added, and the mixture stirred at room temp. overnight. The reaction mixture was diluted with Et2O and washed with saturated Na2S2O3 solution (3 until the organic layer was free of iodine), water, saturated sodium hydrogen carbonate solution and brine. The organic layer was dried with MgSO4, filtered, and concentrated in vacuo. Purification of the crude residue by silica gel flash column chromatography (PE) afforded the allylic iodide. 1-Iodohept-2-ene (4a): By subjecting pentanal (10.0 g, 116 mmol) to the general procedure for the synthesis of allylic iodides, 4a was obtained (eluting in PE) as a pale yellow oil (23.0 g, 103 mmol, 89 % over two steps). Rf = 0.71 (PE/EA, 2:1, v/v). IR (film): = 2956, 2928, 2859, 1458, 970, 741 cm1. 1H NMR (500 MHz, CDCl3): = 5.745.71 (m, 2 H, 2-H and 3-H), 3.913.88 (m, 2 H, 1a-H and 1b-H), 2.04 (dd, J3,4 = J4,5 = 7.0 Hz, 2 H, 4a-H and 4bH), 1.391.24 (m, 4 H, 5-H and 6-H), 0.82 (t, J6,7 = 7.2 Hz, 3 H, 7-CH3) ppm. 13C NMR (125 MHz, CDCl3): = 135.3 (C-2), 127.8 (C-3), 31.7, 30.9, 22.1 (C-4C-6), 13.9 (C-7), 7.1 (C-1) ppm. HRMS (APCI): calcd. for C7H13IH [M + H]+ 225.0140; found 225.0149. 1-Iodotetradec-2-ene (4b): By subjecting dodecanal (1.00 g, 5.42 mmol) to the general procedure for the synthesis of allylic iodides, 4b was obtained (eluting in PE) as a pale yellow oil (1.40 g, 4.39 mmol, 81 % over two steps). Rf = 0.76 (PE/EA, 2:1, v/v). IR (film): = 2955, 2922, 2852, 1464, 961, 721 cm1. 1H NMR (500 MHz, CDCl3): = 5.735.71 (m, 2 H, 2-H and 3-H), 3.90 3.88 (m, 2 H, 1a-H and 1b-H), 2.03 (dd, J3,4 = J4,5 = 7.2 Hz, 2 H, 4a-H and 4b-H), 1.391.27 (m, 18 H, 5-H13-H), 0.82 (t, J6,7 = 7.2 Hz, 3 H, 14-CH3) ppm. 13C NMR (125 MHz, CDCl3): = 135.4 (C-2), 127.7 (C-3), 32.0, 31.9, 29.65, 29.62, 29.60, 29.4, 29.3,
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Scheme 4. Explanation of the stereoselectivity.

Conclusions
We have developed an improved methodology for the synthesis of long-chain -alkylated -hydroxy esters by the use of allylic halides in the FrterSeebach alkylation. This allylic alkylation is highly diastereoselective and, when compared to similar reactions using the corresponding saturated alkyl halides, gives superior yields. The prerequisite allylic iodides were readily prepared in two steps in good yield from the corresponding aldehydes, and the unsaturated -alkylated -hydroxy esters were readily hydrogenated in excellent yield. The final -alkylated -hydroxy esters are, in turn, valuable synthetic intermediates for the preparation of a number of biologically important lipids.

Experimental Section
General Methods: Unless stated otherwise all reactions were performed under an atmosphere of N2. Prior to use, THF was distilled from Na wire and benzophenone, toluene was dried and stored with Na wire, CH2Cl2 was distilled from P2O5 and acetone was dried with K2CO3, distilled and stored over 4 MS. HMPA was dried with CaH2, distilled and stored under nitrogen, diisopropylamine was dried with NaOH, distilled and stored under nitrogen and allyl bromide, allyl iodide and heptyl iodide were dried with MgSO4, distilled and stored under nitrogen. l-()-Malic acid (Sigma), bromotetradecane (Fluka), 1-docosanol (Aldrich), 1-eicosanol (Alfa Aesar), 1 m vinylmagnesium bromide (Aldrich), pentanal (Koch-Light Laboratories), dodecanal (Aldrich), octadecanol (BDH), PPh3 (Merck), I2 (Unilab), Pd/C (Aldrich), H2SO4 (LabScan), ethanol (Pure Science), anhydrous Et2O (Biolab), EtOAc (EA, Pancreac), petroleum ether (PE, Pure Science), CHCl3 998
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Synthesis of Long Chain -Alkyl--Hydroxy-Esters Using Allylic Halides 29.1, 28.8, 22.7 31.7 (C-4C-13), 14.1 (C-14), 7.1 (C-1) ppm. HRMS (APCI): calcd. for C14H27IH [M + H]+ 323.1236; found 323.1242. 1-Iodoeicos-2-ene (4c): By subjecting octadecanal (1.69 g, 6.32 mmol) to the general procedure for the synthesis of allylic iodides, 4c was obtained (eluting in PE) as a white solid (1.80 g, 4.42 mmol, 70 % over two steps). Rf = 0.86 (PE/EA, 2:1, v/v). IR (film): = 2924, 2853, 1464, 961, 738 cm1. 1H NMR (500 MHz, CDCl3): = 5.735.71 (m, 2 H, 2-H and 3-H), 3.893.87 (m, 2 H, 1a-H and 1b-H), 2.03 (dd, J3,4 = J4,5 = 7.2 Hz, 2 H, 4a-H and 4bH), 1.441.22 (m, 30 H, 5-H19-H), 0.89 (t, J6,7 = 6.7 Hz, 3 H, 20CH3) ppm. 13C NMR (125 MHz, CDCl3): = 135.4 (C-2), 127.8 (C-3), 32.1, 31.9, 29.71, 29.68, 29.67, 29.65, 29.6, 29.50, 29.45, 29.3, 29.1, 28.8, 28.7, 26.8, 22.7 (C-4C-19), 14.1 (C-20), 7.1 (C-1) ppm. HRMS (APCI): calcd. for C20H39IH [M + H]+ 407.2175; found 407.2168. 1-Iododocos-2-ene (4d): By subjecting eicosanal (1.20 g, 4.05 mmol) to the general procedure for the synthesis of allylic iodides, 4d was obtained (eluting in PE) as a white solid (1.25 g, 2.87 mmol, 71 % over two steps). Rf = 0.95 (PE/EA, 2:1, v/v). IR (film): = 2922, 2852, 1464, 962, 740 cm1. 1H NMR (500 MHz, CDCl3): = 5.72 5.71 (m, 2 H, 2-H and 3-H), 3.883.87 (m, 2 H, 1a-H and 1b-H), 2.01 (dd, J3,4 = J4,5 = 7.2 Hz, 2 H, 4a-H and 4b-H), 1.431.28 (m, 34 H, 5-H21-H), 0.89 (t, J6,7 = 6.7 Hz, 3 H, 22-CH3) ppm. 13C NMR (125 MHz, CDCl3): = 135.4 (C-2), 127.7 (C-3), 32.0, 31.9, 29.70, 29.67, 29.66, 29.65, 29.58, 29.5, 29.44, 29.36, 29.3, 29.1, 28.8, 28.7, 26.9, 26.8, 22.7 (C-4C-21), 14.1 (C-22), 7.1 (C-1) ppm. HRMS (APCI): calcd. for C22H43IH [M + H]+ 435.2488; found 435.2494. 1-Iodotetracos-2-ene (4e): By subjecting docosanal (3.50 g, 10.8 mmol) to the general procedure for the synthesis of allylic iodides, 4d was obtained (eluting in PE) as a white solid (3.63 g, 7.87 mmol, 73 % over two steps). Rf = 0.95 (PE/EA, 2:1, v/v). IR (film): = 2915, 2848, 1713, 1471, 739 cm1. 1H NMR (500 MHz, CDCl3): = 5.735.71 (m, 2 H, 2-H and 3-H), 3.893.88 (m, 2 H, 1a-H and 1b-H), 2.02 (dd, J3,4 = J4,5 = 6.8 Hz, 2 H, 4a-H and 4bH), 1.371.26 (m, 38 H, 5-H23-H), 0.89 (t, J6,7 = 7.1 Hz, 3 H, 24CH3) ppm. 13C NMR (125 MHz, CDCl3): = 135.4 (C-2), 127.8 (C-3), 32.0, 31.9, 29.72, 29.69, 29.68, 29.67, 29.60, 29.47, 29.39, 29.1, 28.8, 22.7 (C-4C-23), 14.1 (C-24), 7.1 (C-1) ppm. HRMS (APCI): calcd. for C24H47IH [M + H]+ 463.2801; found 463.2805. General Procedure for the Synthesis of -Alkenyl--Hydroxy Diesters: nBuLi (2.0 m in hexanes, 11.5 mL, 23.0 mmol) was added to a solution of diisopropylamine (6.3 mL, 25.0 mmol) in THF (20 mL) at 0 C. After 30 min, the solution was cooled to 78 C and 5 (1.9 g, 10 mmol) in THF (20 mL) was added. The resulting mixture was stirred at 78 C for 1 h, warmed to 20 C over 1 h and stirred at 20 C for 20 min. After cooling to 78 C, the allylic iodide (15.0 mmol, 1.5 equiv.) in THF (20 mL) was added dropwise, and the reaction was stirred for 1 h at 50 C and a further 1 h during which time the temperature increased to 20 C. The reaction was then quenched with saturated NH4Cl solution and extracted with EtOAc (3 100 mL). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried (MgSO4), filtered, and the solvent was removed in vacuo to yield a yellow oil. Purification of the residue using silica gel flash column chromatography gave the alkylated product. Ethyl (2S)-Hydroxy-(3R)-ethoxycarbonylhex-4-enoate (anti-6a): By the reaction of 5 (3.96 g, 20.9 mmol) with allyl bromide (2.64 mL, 31.25 mmol) according to the general procedure for the synthesis of -alkenyl--hydroxy diesters, 6a was obtained (eluting in 10:1, PE/EA, v/v) as a colourless oil (2.72 g, 11.9 mmol, 57 %, anti/syn =
Eur. J. Org. Chem. 2012, 9951002

14:1). Rf = 0.39 (PE/EA, 2:1, v/v). []23 D = +13.0 (c = 2.23, CHCl3), Ref.[34] []20 = 3079, 2982, D = +11.3 (c = 2.23, CHCl3). IR (film): 2961, 2924, 1733, 1643, 1132, 1099, 1031, 736, 703 cm1. 1H NMR (500 MHz, CDCl3): = 5.75 (ddt, J5,6-trans = 17.1 Hz, J5,6-cis = 10.2 Hz, J4a,5 = J4b,5 = 7.5 Hz, 1 H, 5-H), 5.11 (d, J5,6-trans = 17.1 Hz, 1 H, 6-trans-H), 5.05 (d, J5,6-cis = 10.2 Hz, 1 H, 6-cis-H), 4.254.14 (m, 3 H, CH2O-1 and 2-H), 4.124.01 (m, 2 H, 3CO2CH2), 2.90 (m, 1 H, 3-H), 2.56 (ddd, J4a,4b = 14.4 Hz, J3,4a = J4a,5 = 7.5 Hz, 1 H, 4a-H), 2.38 (ddd, J4a,4b = 14.4 Hz, J3,4b = J4b,5 = 7.5 Hz, 1 H, 4b-H), 1.24 (t, J = 7.1 Hz, 3 H, CH3, 1-OEt), 1.17 (t, J = 7.0 Hz, 3 H, CH3, 3-CO2Et) ppm. 13C NMR (125 MHz, CDCl3): = 173.6 (C-1), 172.0 (CO2-3), 134.9 (C-5), 118.0 (C-6), 70.2 (C-2), 61.9 (CH2O, OEt-1), 61.0 (CH2O, CO2CH2-3), 48.1 (C3), 32.2 (C-4), 14.1 (CH3, OEt-1), 14.1 (CH3, CO2Et-3) ppm. HRMS (ESI): calcd. for C11H18O5Na [M + Na]+ 253.1052; found 253.1055. Ethyl (2S)-Hydroxy-(3R)-ethoxycarbonyldecen-5-enoate (anti-6c): By the reaction of 5 (3.98 g, 20.9 mmol) with 1-iodohept-2-ene (7.03 g, 31.42 mmol) according to the general procedure for the synthesis of -alkenyl--hydroxy diesters, 6c was obtained (eluting in 15:1, PE/EA, v/v) as a colourless oil (3.28 g, 11.5 mmol, 55 %, anti/syn = 9:1). Rf = 0.42 (PE/EA, 2:1, v/v). []23 D = +19.0 (c = 1.0, CHCl3). IR (film): = 3234, 2983, 2960, 2929, 1734, 1466, 1374, 1198, 861, 736 cm1. 1H NMR (500 MHz, CDCl3): = 5.57 (dt, J5,6 = 15.2 Hz, J6,7a = J6,7b = 6.6 Hz, 1 H, 6-H), 5.39 (dt, J5,6 = 15.2 Hz, J4a,5 = J4b,5 = 6.2 Hz, 1 H, 5-H), 4.214.31 (m, 3 H, 1CH2O and 2-H), 4.164.10 (m, 2 H, 3-CO2CH2), 2.90 (ddd, J3,4a = J3,4b = 8.3 Hz, J2,3 = 3.2 Hz, 1 H, 3-H), 2.582.51 (m, 1 H, 4a-H), 2.38 (ddd, J4a,4b = 14.4 Hz, J3,4b = 8.3 Hz, J4b,5 = 6.2 Hz, 1 H, 4bH), 2.01 (q, J6,7 = J7,8 = 6.6 Hz, 2 H, 7-H), 1.331.27 (m, 4 H, 8H and 9-H), 1.24 (t, J = 7.3 Hz, 6 H, 2 CH3), 0.88 (t, J = 7.2 Hz, 3 H, 10-CH3) ppm. 13C NMR (125 MHz, CDCl3): = 173.7 (C1), 172.3 (CO2-3), 134.4 (C-6), 125.9 (C-5), 70.2 (C-2), 61.8 (CH2O, OEt-1), 60.8 (CH2O, CO2CH2-3), 48.6 (C-3), 32.2 (C-4), 31.5 (C7), 31.1 (C-8), 22.2 (C-9), 14.2 (C-10), 14.1 (CH3, OEt-1), 14.1 (CH3, CO2Et-3) ppm. HRMS (ESI): calcd. for C15H26O5Na [M + Na]+ 309.1678; found 309.1682. Ethyl (2S)-Hydroxy-(3R)-ethoxycarbonylheptadecen-5-enoate (anti6e): By the reaction of 5 (3.99 g, 21.0 mmol) with 1-iodotetradec2-ene (10.14 g, 31.5 mmol) according to the general procedure for the synthesis of -alkenyl--hydroxy diesters, 6e was obtained (eluting in 15:1, PE/EA, v/v) as a colourless oil (4.11 g, 10.7 mmol, 51 %, anti/syn = 10:1). Rf = 0.5 (PE/EA, 2:1, v/v). []23 D = +2.0 (c = 0.1, CHCl3). IR (film): = 3522, 2924, 2853, 1737, 1219, 1032, 772 cm1. 1H NMR (500 MHz, CDCl3): = 5.57 (dt, J5,6 = 15.1 Hz, J6,7a = J6,7b = 7.1 Hz, 1 H, 6-H), 5.39 (dt, J5,6 = 15.1 Hz, J4a,5 = J4b,5 = 7.2 Hz, 1 H, 5-H), 4.314.20 (m, 3 H, 1-CH2O and 2-H), 4.164.11 (m, 2 H, 3-CO2CH2), 3.18 (d, J2,OH = 7.4 Hz, 1 H, OH), 2.90 (ddd, J3,4a = J3,4b = 8.3 Hz, J2,3 = 3.2 Hz, 1 H, 3-H), 2.582.51 (m, 1 H, 4a-H), 2.38 (ddd, J4a,4b = 14.2 Hz, J3,4b = 8.3 Hz, J4b,5 = 7.2 Hz, 1 H, 4b-H), 1.99 (q, J6,7 = J7,8 = 7.1 Hz, 2 H, 7-H), 1.321.23 (m, 24 H, 8-H16-H and 2 CH3), 0.88 (t, J = 7.2 Hz, 3 H, 17-CH3) ppm. 13C NMR (125 MHz, CDCl3): = 173.7 (C-1), 172.3 (3-CO2), 134.4 (C-6), 125.8 (C-5), 70.2 (C-2), 61.8 (CH2O, OEt-1), 60.8 (CH2O, CO2CH2-3), 48.6 (C-3), 32.2 (C4), 31.9 (C-7), 31.1 (C-8), 29.7, 29.6, 29.6, 29.5, 29.4, 29.3, 29.2, 22.68 (C-9C-16), 14.1 (C-17), 14.1 (CH3, OEt-1), 14.1 (CH3, CO2Et-3) ppm. HRMS (ESI): calcd. for C22H40O5Na [M + Na]+ 407.2773; found 407.2781. Ethyl (2S)-Hydroxy-(3R)-ethoxycarbonyltricos-5-enoate (anti-6g): By the reaction of 5 (0.40 g, 2.11 mmol) with 1-iodoeicos-2-ene (1.28 g, 3.16 mmol) according to the general procedure for the synwww.eurjoc.org

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FULL PAPER
thesis of -alkenyl--hydroxy diesters, 6g was obtained (eluting in 15:1, PE/EA, v/v) as white solid (0.48 g, 1.03 mmol, 49 %, anti/syn = 9:1). Rf = 0.49 (PE/EA, 2:1, v/v). []22 D = +6.0 (c = 1.0, CHCl3). IR (film): = 3517, 2924, 2853, 1737, 1219, 1032, 970, 772 cm1. 1 H NMR (500 MHz, CDCl3): = 5.56 (dt, J5,6 = 15.4 Hz, J6,7a = J6,7b = 6.6 Hz, 1 H, 6-H), 5.40 (dt, J5,6 = 15.4 Hz, J4a,5 = J4b,5 = 6.6 Hz, 1 H, 5-H), 4.314.22 (m, 3 H, 1-CH2O and 2-H), 4.194.10 (m, 2 H, 3-CO2CH2), 2.90 (ddd, J3,4a = J3,4b = 8.8 Hz, J2,3 = 3.2 Hz, 1 H, 3-H), 2.582.52 (m, 1 H, 4a-H), 2.38 (ddd, J4a,4b = 15.2 Hz, J3,4b = 8.8 Hz, J4b,5 = 6.6 Hz, 1 H, 4b-H), 1.99 (q, J6,7 = J7,8 = 6.6 Hz, 2 H, 7a,b-H), 1.321.23 (m, 36 H, 8-H22-H and 2 CH3), 0.89 (t, J = 7.1 Hz, 3 H, 23-CH3) ppm. 13C NMR (125 MHz, CDCl3): = 173.7 (C-1), 172.3 (3-CO2), 134.4 (C-6), 125.8 (C-5), 70.2 (C-2), 61.8 (CH2O, OEt-1), 60.8 (CH2O, CO2CH2-3), 48.6 (C3), 32.2 (C-4), 31.9 (C-7), 31.1 (C-8), 29.7, 29.66, 29.65, 29.5, 29.4, 29.2, 22.7 (C-9C-22), 14.1 (C-23), 14.1 (CH3, OEt-1), 14.1 (CH3, CO2Et-3) ppm. HRMS (ESI): calcd. for C28H52O5Na [M + Na]+ 491.3712; found 491.3706. Ethyl (2S)-Hydroxy-(3R)-ethoxycarbonylpentacos-5-enoate (anti6i): By the reaction of 5 (0.53 g, 2.77 mmol) with 1-iododocos-2ene (1.80 g, 4.15 mmol) according to the general procedure for the synthesis of -alkenyl--hydroxy diesters, 6i was obtained (eluting in 15:1, PE/EA, v/v) as a white solid (0.57 g, 1.16 mmol, 42 %, anti/syn = 9:1). Rf = 0.6 (PE/EA, 2:1, v/v). []23 D = +5.0 (c = 1.0, CHCl3). IR (film): = 3523, 2916, 2849, 1735, 1373, 1213, 1032, 969, 756 cm1. 1H NMR (500 MHz, CDCl3): = 5.56 (dt, J5,6 = 15.1 Hz, J6,7a = J6,7b = 6.9 Hz, 1 H, 6-H), 5.39 (dt, J5,6 = 15.1 Hz, J4a,5 = J4b,5 = 7.3 Hz, 1 H, 5-H), 4.304.22 (m, 3 H, CH2O-1 and 2-H), 4.144.10 (m, 2 H, 3-CO2CH2), 3.18 (d, J2,OH = 6.9 Hz, 1 H, OH), 2.90 (ddd, J3,4a = J3,4b = 8.3 Hz, J2,3 = 3.2 Hz, 1 H, 3-H), 2.582.52 (m, 1 H, 4a-H), 2.38 (ddd, J4a,4b = 14.1 Hz, J3,4a = 8.3 Hz, J4a,5 = 7.3 Hz, 1 H, 4b-H), 1.99 (q, J6,7 = J7,8 = 6.9 Hz, 2 H, 7a,b-H), 1.331.21 (m, 40 H, 8-H24-H and 2 CH3), 0.88 (t, J = 7.2 Hz, 3 H, 25-CH3) ppm. 13C NMR (125 MHz, CDCl3): = 173.7 (C-1), 172.3 (3-CO2), 134.5 (C-6), 125.8 (C-5), 70.2 (C-2), 61.8 (CH2O, OEt-1), 60.8 (CH2O, CO2CH2-3), 48.6 (C-3), 32.5 (C4), 31.9 (C-7), 31.1 (C-8), 29.7, 29.66, 29.64, 29.5, 29.4, 29.2, 22.7 (C-9C-24), 14.1 (C-25), 14.1 (CH3, OEt-1), 14.1 (CH3, CO2Et-3) ppm. HRMS (ESI): calcd. for C30H56O5Na [M + Na]+ 519.4025; found 519.4029. Ethyl (2S)-Hydroxy-(3R)-ethoxycarbonylheptacos-5-enoate (anti6j): By the reaction of 5 (0.55 g, 2.89 mmol) with 1-iodotetracos-2ene (2.0 g, 4.32 mmol) according to the general procedure for the synthesis of -alkenyl--hydroxy diesters, 6j was obtained (eluting in 15:1, PE/EA, v/v) as a white solid (0.62 g, 1.19 mmol, 41 %, anti/syn = 9:1). Rf = 0.58 (PE/EA, 2:1, v/v). []22 D = +0.1 (c = 1.0, CHCl3). IR (film): = 3351, 2922, 2852, 1736, 1376, 1215, 1042, 756 cm1. 1H NMR (500 MHz, CDCl3): = 5.56 (dt, J5,6 = 15.1 Hz, J6,7a = J6,7b = 6.8 Hz, 1 H, 6-H), 5.39 (dt, J5,6 = 15.1 Hz, J4a,5 = J4b,5 = 6.5 Hz, 1 H, 5-H), 4.304.22 (m, 3 H, 1-CH2O and 2-H), 4.164.12 (m, 2 H, 3-CO2CH2), 3.17 (d, J2,OH = 7.3 Hz, 1 H, OH), 2.91 (ddd, J3,4a = J3,4b = 9.1 Hz, J2,3 = 3.2 Hz, 1 H, 3-H), 2.582.53 (m, 1 H, 4a-H), 2.38 (ddd, J4a,4b = 14.3 Hz, J3,4a = 9.1 Hz, J4a,5 = 6.5 Hz, 1 H, 4b-H), 2.00 (q, J6,7 = J7,8 = 7.8 Hz, 2 H, 7a,b-H), 1.371.18 (m, 44 H, 8-H26-H and 2 CH3), 0.88 (t, J = 6.8 Hz, 3 H, 27-CH3) ppm. 13C NMR (125 MHz, CDCl3): = 173.7 (C-1), 172.3 (3-CO2), 134.5 (C-6), 125.8 (C-5), 70.2 (C-2), 61.8 (CH2O, OEt-1), 60.8 (CH2O, CO2CH2-3), 48.6 (C-3), 32.6 (C4), 31.9 (C-7), 31.1 (C-8), 29.71, 29.67, 29.65, 29.58, 29.52, 29.37, 29.2, 22.7 (C-9C-26), 14.2 (C-27), 14.1 (CH3, OEt-1), 14.1 (CH3, CO2Et-3) ppm. HRMS (ESI): calcd. for C32H60O5Na [M + Na]+ 547.4338; found 547.4344. 1000
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A. A. Khan, S. H. Chee, B. L. Stocker, M. S. M. Timmer General Procedure for the Synthesis of -Alkyl--Hydroxy Diesters: nBuLi (2.0 m in hexanes, 11.5 mL, 23.0 mmol) was added to a solution of diisoproplyamine (6.3 mL, 25.0 mmol) in THF (20 mL) at 0 C. After 30 min, the solution was cooled to 78 C and 5 (1.9 g, 10 mmol) in THF (20 mL) was added. The resulting mixture was stirred at 78 C for 1 h, warmed to 20 C over 1 h and stirred at 20 C for 20 min. After cooling to 78 C, alkyl iodide (15.0 mmol, 1 equiv.) in THF (20 mL) was added dropwise, and the reaction stirred for 2 h, during which time the temperature increased to 0 C, and stirred for a further 2 h at room temperature. The reaction was quenched using saturated NH4Cl solution and extracted with EtOAc (3 100 mL). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried (MgSO4), filtered, and the solvent was removed in vacuo to yield a yellow oil. Purification of the residue by flash column chromatography gave the alkylated product. Ethyl (2S)-Hydroxy-(3R)-ethoxycarbonyldecanoate (anti-6b): By the reaction of 5 (3.97 g, 20.9 mmol) with 1-iodoheptane (5.13 mL, 31.3 mmol) according to the general procedure for the synthesis of -alkylated--hydroxy diesters, 6b was obtained (eluting in 15:1, PE/EA, v/v) as a colourless oil (2.24 g, 7.4 mmol, 37 %, anti/syn = 7:1). Rf = 0.73 (PE/EA, 2:1, v/v). []23 D = +0.7 (c = 0.1, CHCl3). IR (film): = 3522, 3020, 2928, 2857, 1734, 1376, 1216, 1027, 754, 668 cm1. 1H NMR (500 MHz, CDCl3): = 4.314.21 (m, 3 H, 1CH2O and 2-H), 4.14 (q, Ja,b = 7.1 Hz, 2 H, CH2O, 3-CO2CH2), 3.19 (d, J2,OH = 7.6 Hz, 1 H, OH), 2.84 (td, J3,4 = 7.1 Hz, J2,3 = 3.7 Hz, 1 H, 3-H), 1.85 (ddt, J4a,4b = 14.9 Hz, J3,4a = J4a,5a = J4a,5b = 7.1 Hz, 1 H, 4a-H), 1.66 (ddt, J4a,4b = 14.9 Hz, J3,4b = J4b,5a = J4b,5b = 7.1 Hz, 1 H, 4b-H), 1.401.24 (m, 16 H, 5-H9-H, 2 CH3), 0.89 (t, J = 6.9 Hz, 3 H, 10-CH3) ppm. 13C NMR (125 MHz, CDCl3): = 173.5 (C-1), 172.9 (CO2-3), 71.1 (C-2), 61.8 (CH2O, OEt-1), 60.8 (CH2O, CO2CH2-3), 48.6 (C-3), 31.8 (C-4), 29.4, 29.1, 28.1, 27.4, 22.6 (C-5C-9), 14.1 (C-10), 14.1 (CH3, OEt-1), 14.1 (CH3, CO2Et-3) ppm. HRMS (ESI): calcd. for C15H28O5Na [M + Na]+ 311.1833; found 311.1834. Ethyl (2S)-Hydroxy-(3R)-ethoxycarbonylheptadecanoate (anti-6d): By the reaction of 5 (0.44 g, 2.35 mmol) with 1-iodotetradecane (1.14 g, 3.53 mmol) according to the general procedure for the synthesis of -alkyl--hydroxy diesters, 6d was obtained (eluting in 15:1, PE/EA, v/v) as a colourless oil (0.14 g, 0.34 mmol, 15 %, anti/syn = 9:1). Rf = 0.66 (PE/EA, 2:1, v/v). []23 D = +4.0 (c = 1.0, CHCl3). IR (film): = 3514, 3020, 2925, 2584, 1735, 1466, 1369, 1216, 755 cm1. 1H NMR (500 MHz, CDCl3): = 4.294.22 (m, 3 H, 1-CH2O and 2-H), 4.14 (q, J = 7.1 Hz, 2 H, 3-CO2CH3), 3.19 (d, J2,OH = 7.6 Hz, 1 H, OH), 2.84 (td, J3,4 = 7.2 Hz, J2,3 = 3.5 Hz, 1 H, 3-H), 1.83 (ddt, J4a,4b = 14.0 Hz, J3,4a = J4a,5a = J4a,5b = 7.2 Hz, 1 H, 4a-H), 1.66 (ddt, J4a,4b = 14.0 Hz, J3,4b = J4b,5a = J4b,5b = 7.2 Hz, 1 H, 4b-H), 1.451.21 (m, 30 H, 5-H16-H and 2 CH3), 0.87 (t, J = 6.4 Hz, 3 H, 17-CH3) ppm. 13C NMR (125 MHz, CDCl3): = 173.5 (C-1), 172.9 (CO2-3), 71.1 (C-2), 61.8 (CH2O, OEt-1), 60.8 (CH2O, CO2CH2-3), 48.6 (C-3), 31.9 (C-4), 29.74, 29.73, 29.71, 29.70, 29.64, 29.62, 29.4, 28.1, 27.4, 22.7 (C-5C-16), 14.2 (C-17), 14.1 (CH3, OEt-1), 14.1 (CH3, CO2Et-3) ppm. HRMS (ESI): calcd. for C22H42O5Na [M + Na]+ 409.2931; found 409.2928. Ethyl (2S)-Hydroxy-(3R)-ethoxycarbonyltricosanoate (anti-6f): By the reaction of 5 (0.22 g, 1.15 mmol) with 1-iodoeicosane (0.70 g, 1.72 mmol) according to the general procedure for the synthesis of -alkyl--hydroxy diesters, 6f was obtained (eluting in 15:1, PE/EA, v/v) as a white solid (0.02 g, 0.05 mmol, 4 %, anti/syn = 6:1). Rf = 0.58 (PE/EA, 2:1, v/v). []23 D = +2.0 (c = 1.0, CHCl3). IR (film): = 2918, 2850, 1737, 1252, 1182, 1099, 1030, 837, 757 cm1. 1H NMR (500 MHz, CDCl3): = 4.314.21 (m, 3 H, 1-CH2O and 2Eur. J. Org. Chem. 2012, 9951002

2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Synthesis of Long Chain -Alkyl--Hydroxy-Esters Using Allylic Halides H), 4.184.12 (m, 2 H, 3-CO2CH3), 3.20 (d, J2,OH = 7.8 Hz, 1 H, OH), 2.84 (td, J3,4 = 7.8 Hz, J2,3 = 3.7 Hz, 1 H, 3-H), 1.83 (ddt, J4a,4b = 14.4 Hz, J3,4a = J4a,5a = J4a,5b = 7.8 Hz, 1 H, 4a-H), 1.66 (ddt, J4a,4b = 14.4 Hz, J3,4b = J4b,5a = J4b,5b = 7.8 Hz, 1 H, 4b-H), 1.391.23 (m, 42 H, 5-H22-H and 2 CH3), 0.89 (t, J = 6.9 Hz, 3 H, 23-CH3) ppm. 13C NMR (125 MHz, CDCl3): = 173.5 (C1), 172.9 (CO2-3), 71.0 (C-2), 61.8 (CH2O, OEt-1), 60.8 (CH2O, CO2CH2-3), 48.6 (C-3), 31.9 (C-4), 29.68, 29.66, 29.64, 29.62, 29.5, 29.4, 29.3, 28.1, 27.4, 22.7 (C-5C-22), 14.2 (C-23), 14.1 (CH3, OEt-1), 14.1 (CH3, CO2Et-3) ppm. HRMS (ESI): calcd. for C28H54O5Na [M + Na]+ 493.3869; found 493.3871. Ethyl (2S)-Hydroxy-(3R)-ethoxycarbonylpentacosanoate (anti-6h): By the reaction of 5 (0.22 g, 1.16 mmol) with 1-iododocosane (0.78 g, 1.77 mmol) according to the general procedure for the synthesis of -alkyl--hydroxy diesters, 6h was obtained (eluting in 15:1, PE/EA, v/v) as a white solid (0.05 g, 0.096 mmol, 8 %, anti/syn = 6:1). Rf = 0.58 (PE/EA, 2:1, v/v). []22 D = +3.0 (c = 0.1, CHCl3). IR (film): = 3473, 2917, 2850, 1737, 1599, 2032, 837, 758, 721, 668 cm1. 1H NMR (500 MHz, CDCl3): = 4.304.21 (m, 3 H, 1CH2O and 2-H), 4.14 (m, 2 H, 3-CO2CH2), 3.20 (d, J2,OH = 7.6 Hz, 1 H, 2-OH), 2.84 (td, J3,4 = 7.2 Hz, J2,3 = 3.7 Hz, 1 H, 3-H), 1.83 (ddt, J4a,4b = 14.2 Hz, J3,4a = J4a,5a = J4a,5b = 7.2 Hz, 1 H, 4a-H), 1.66 (ddt, J4a,4b = 14.2 Hz, J3,4b = J4b,5a = J4b,5b = 7.2 Hz, 1 H, 4bH), 1.401.24 (m, 46 H, 5-H24-H, 2 CH3), 0.89 (t, J = 6.6 Hz, 3 H, 25-CH3) ppm. 13C NMR (125 MHz, CDCl3): = 173.5 (C1), 172.9 (CO2-3), 71.1 (C-2), 61.8 (CH2O, OEt-1), 60.8 (CH2O, CO2CH2-3), 48.6 (C-3), 31.9 (C-4), 29.7, 29.7, 29.7, 29.6, 29.4, 29.4, 28.1, 27.4, 22.7 (C-5C-24), 14.2 (C-25), 14.1 (CH3, OEt-1), 14.1 (CH3, CO2Et-3) ppm. HRMS (ESI): calcd. for C30H58O5Na [M + Na]+ 521.4182; found 521.4180. General Procedure for Hydrogenation: Pd/C (5 wt.-%) was added to a solution of the allylic alkylated diester (1 mmol) in a mixture of CH2Cl2/EtOH (10 mL, 1:1, v/v) and stirred at room temperature under H2 overnight. The reaction mixture was filtered through Celite, the Celite was washed thoroughly with CH2Cl2/EtOH (20 mL, 1:1, v/v), and the filtrate was concentrated in vacuo. The product was purified by flash chromatography. Ethyl (2S)-Hydroxy-(3R)-ethoxycarbonyldecanoate (anti-6b): By subjecting 6c (anti/syn = 9:1, 2.01 g, 6.99 mmol) to the general procedure for hydrogenation, pure anti- 6b was obtained (eluting in 15:1 PE/EA, v/v) as a colourless oil (1.81 g, 6.29 mmol, 90 %). The spectroscopic data matched those reported earlier. Ethyl (2S)-Hydroxy-(3R)-ethoxycarbonylheptadecanoate (anti-6d): By subjecting 6e (anti/syn = 10:1, 3.60 g, 9.38 mmol) to the general procedure for hydrogenation, pure anti-6d was obtained (eluting in 15:1, PE/EA, v/v) as a colourless oil (3.29 g, 8.52 mmol, 91 %). The spectroscopic data matched those reported earlier. Ethyl (2S)-Hydroxy-(3R)-ethoxycarbonyltricosanoate (anti-6f): By subjecting 6g (anti/syn = 9:1, 0.40 g, 0.85 mmol) to the general procedure for hydrogenation, pure anti-6f was obtained (eluting in 15:1, PE/EA, v/v) as a white solid (0.36 g, 0.77 mmol, 90 %). The spectroscopic data matched those reported earlier. Ethyl (2S)-Hydroxy-(3R)-ethoxycarbonylpentacosanoate (anti-6h): By subjecting 6i (anti/syn = 9:1, 0.80 g, 1.61 mmol) to the general procedure for hydrogenation, pure anti-6h was obtained (eluting in 15:1, PE/EA, v/v) as a white solid (0.72 g, 1.45 mmol, 90 %). The spectroscopic data matched those reported earlier. Ethyl (2S)-Hydroxy-(3R)-ethoxycarbonylheptacosanoate (anti-6k): By subjecting 6j (anti/syn = 9:1, 0.11 g, 0.21 mmol) to the general procedure for hydrogenation, pure anti-6k was obtained (eluting in 15:1, PE/EA, v/v) as a white solid (0.10 g, 0.19 mmol, 90 %). Rf =
Eur. J. Org. Chem. 2012, 9951002

0.54 (PE/EA, 2:1, v/v). []D 22 = +2.0 (c = 0.1, CHCl3). IR (film): = 3473, 2917, 2850, 1737, 1208, 1029, 771, 668 cm1. 1H NMR (500 MHz, CDCl3): = 4.304.20 (m, 3 H, 1-CH2O and 2-H), 4.184.12 (m, 2 H, 3-CO2CH2), 3.20 (d, J2,OH = 7.9 Hz, 1 H, 2OH), 2.84 (td, J3,4 = 7.3 Hz, J2,3 = 3.7 Hz, 1 H, 3-H), 1.83 (ddt, J4a,4b = 13.9 Hz, J3,4a = J4a,5a = J4a,5b = 7.3 Hz, 1 H, 4a-H), 1.66 (ddt, J4a,4b = 13.9 Hz, J3,4b = J4b,5a = J4b,5b = 7.3 Hz, 1 H, 4b-H), 1.431.24 (m, 50 H, 5-H26-H, 2 CH3), 0.89 (t, J = 6.8 Hz, 3 H, CH3-27) ppm. 13C NMR (125 MHz, CDCl3): = 173.5 (C-1), 172.9 (CO2-3), 71.0 (C-2), 61.8 (CH2O, OEt-1), 60.8 (CH2O, CO2CH23), 48.6 (C-3), 31.9 (C-4), 29.7, 29.68, 29.67, 29.65, 29.58, 29.45, 29.37, 28.1, 27.4, 22.7 (C-5C-26), 14.2 (C-27), 14.1 (CH3, OEt-1 and CH3, CO2Et-3) ppm. HRMS (ESI): calcd. for C32H62O5Na [M + Na]+ 549.4495; found 549.4490. Cross-Metathesis for the Preparation of Ethyl (2S)-Hydroxy-(3R)ethoxycarbonylheptadecanoate (anti-6d): To a solution of anti-6a (0.106 g, 0.46 mmol) in CH2Cl2 (2.5 mL) was added Grubbs second-generation catalyst (0.02 g, 0.023 mmol) followed by 1-tridecene (0.11 mL, 0.46 mmol), and the reaction mixture was heated to reflux under nitrogen for 14 h before being cooled and reduced in vacuo. The resulting crude product was purified by column chromatography to yield anti-6e (eluting in 15:1, PE/EA, v/v) as a colourless oil (0.07 g, 0.19 mmol, 41 %). Subsequent hydrogenation of anti-6e according to the above procedure yielded pure anti-6d (0.07 g, 0.18 mmol, 99 %) as a colourless oil. The spectroscopic data matched those reported above. (2S)-Hydroxy-(3R)-ethoxycarbonyldecanol (7): Borane dimethylsulfide complex (1 m in THF, 0.93 mL, 0.93 mmol) was slowly added to a solution of anti-6b (0.24 g, 0.84 mmol) in THF (2 mL). The reaction was stirred at room temp. for 1 h, cooled to 40 C and stirred for 10 min. NaBH4 (0.002 g, 0.04 mmol) was added, and the reaction was warmed to room temperature overnight before being quenched with Dowex H+ (10 % by weight) and ethanol (3 mL). The reaction mixture was filtered, washed (EtOH) and concentrated in vacuo. The residue was dissolved in toluene/ethanol (1:1, 5 mL) and concentrated (repeated 3) in order to remove ethanol and boron as B(OEt)3. The resulting crude oil was purified by flash column chromatography (eluting in 3:1, PE/EA, v/v) to give 7 as a colourless oil (0.12 g, 0.51 mmol, 60 %). Rf = 0.41 (PE/EA, 1 1:1, v/v). []20 D = 11.0 (c = 0.1, CHCl3). H NMR (500 MHz, CDCl3): = 4.20 (q, J = 6.8 Hz, 2 H, 3-CO2CH2), 3.843.83 (m, 2 H, 2-H), 3.69 (bd, J1a,1b = 11.0 Hz, 1 H, 1a-H), 3.55 (dd, J1a,1b = 11.0 Hz, J1b,2 = 7.0 Hz, 1 H, 1b-H), 2.53 (q, J2,3 = J3,4a = J3,4b = 8.0 Hz, 1 H, 3-H), 1.691.60 (m, 1 H, 4a-H), 1.591.55 (m, 1 H, 4b-H), 1.311.28 (m, 13 H, 5-H9-H, CH3), 0.88 (t, J9,10 = 7.1 Hz, 3 H, 10-CH3) ppm. 13C NMR (125 MHz, CDCl3): = 175.5 (CO23), 72.6 (C-2), 65.1 (C-1), 60.8 (CH2O, CO2CH2-3), 47.5 (C-3), 29.3 (C-4), 31.7, 29.4, 29.1, 27.1, 22.6 (C-5C-9), 14.2 (C-10), 14.1 (CH3, CO2Et-3) ppm. HRMS (ESI): calcd. for C13H26O4Na [M + Na]+ 269.1729; found 269.1733. Supporting Information (see footnote on the first page of this article): Characterisation data and copies of the 1H NMR and 13C NMR spectra.

Acknowledgments
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