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FULL PAPER

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] andMattie 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 -hy-

droxy 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 theview that the greater reactivity of the allylic system would

Introduction

The FrterSeebach alkylation provides a convenient en-try to -alkylated -hydroxy esters and is a crucial step inthe preparation of a variety of biologically important com-pounds, which include natural products[13] and derivativesthereof,[47] enzyme inhibitors[8,9] and other key chiralbuilding blocks.[10,11] In Frters early studies, ethyl (S)-3-

hydroxybutyrate was alkylated with methyl, allyl, butyl andbenzyl bromide to give the corresponding (2S,3S)-alkylatedproducts in good yield and excellent diastereoselectiv-ity,[12,13] and the methodology was also used for the alkyl-ation of ethyl (R)-3-hydroxyvalerate using propyl iodide asthe electrophile.[14] At approximately the same time, See-bach also performed pioneering studies in this field, illus-trated by the alkylation of malic acid diesters with methyl,allyl and benzyl halides.[15]

Despite the versatility of the FrterSeebach alkylationin organic synthesis and its potential for the highly dia-stereoselective 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 my-colic acids found on the cell wall of M. tuberculosis andother related mycobacteria (e.g. 1; Figure 1),[19,20] Baird andcoworkers observed that -alkylations using tetra-

[a] School of Chemical and Physical Sciences,Victoria University of Wellington,P. O. Box 600, Wellington, New ZealandFax: +644-463-5237E-mail: [email protected]

[email protected][b] Malaghan Institute of Medical Research,

P. O. Box 7060, Wellington, New ZealandSupporting information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.201101472.

Eur. J. Org. Chem. 2012, 9951002 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 995

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 analo-

gous 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 foundon the cell wall of M. tuberculosis.

cosanyl iodide by the FrterSeebach reaction gave onlymodest yields (31%) of the corresponding -alkylated -hydroxy esters.[16,17] The group later developed a chain-elongation strategy (involving an -alkylation using allyl io-dide followed by ozonolysis and Wittig reactions) in subse-quent mycolic acid syntheses.[2123] Similarly, Nishizawa etal. had no success when performing a FrterSeebach alky-lation using eicosanyl iodide on a tetracosanoyl -hydroxy

functionalised ester, however, they observed that a changeof ester substrate resulted in product formation.[18] Our ownattempts at an -alkylation using eicosanyl iodide gave adisappointing 5% yield. This illustrates the substrate-speci-ficity and fickleness of the methodology when using lipo-philic electrophiles.

Figure 1. Representative mycolic acids.

Given the variable success of the FrterSeebach meth-

odology when using long-chain alkyl halides, we considered

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A. A. Khan, S. H. Chee, B. L. Stocker, M. S. M. TimmerFULL PAPER

developing a strategy whereby allyl halides are used as elec-trophiles. Allyl halides have excellent reactivity, which arisesfrom stereoelectronic interactions between the *CX or-bital and the adjacent system.[2426] In the transition statefor the SN2 reaction of an allylic halide, the overlap betweenthe p orbital on the carbon atom at which displacementoccurs and the p orbitals of the conjugated double bondallows the electron density of the system to be delocalisedover the three carbon atoms involved in the allylic system.This, in turn, leads to a lower transition state energy whencompared to the transition state of a corresponding satu-rated halide. Accordingly, we proposed that a FrterSeeb-ach alkylation using highly reactive long-chain allylic iod-ides would lead to more efficient -alkylations. Our studiesto support this hypothesis are presented herein.

Results and Discussion

To prepare the required allylic iodides, we adopted anefficient two-step strategy that first involved the Grignardaddition of vinylmagnesium bromide to an aldehyde[24] anda subsequent SN2 substitution of the in situ-generatedalkoxytriphenylphosphonium iodide intermediate[27]

(Scheme 1). The starting aldehydes, pentanal (2a) and do-decanal (2b), were sourced commercially, whereas octadec-anal (2c), eicosanal (2d) and docosanal (2e) were preparedby a PCC oxidation of the corresponding alcohols.[28] Forall aldehydes, the Grignard addition proceeded smoothly togive the corresponding allylic alcohols 3ae, though itshould 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 performedat 0 C in toluene.[30] The intermediate allylic alcohols 3ae were subjected to filtration through a short silica gel plugand immediately used. Although the alcohols can be puri-fied by flash column chromatography, they are prone to de-composition[27] and storage is not recommended. Treatmentof each alcohol with a solution of PPh3 and I2 in THF gavethe corresponding allylic iodides 4a (n = 3), 4b (n = 10), 4c(n = 16), 4d (n = 18) and 4e (n = 20) in 89, 81, 70, 71 and73% yield, respectively, over two steps. Each of the allyliciodides 4ae were formed as an inseparable isomeric mix-ture that consisted mainly of the E isomer (E/Z ca. 4:1), asdetermined by the 18.6 vs. 8.5 Hz coupling constant for the

alkene protons in the 1H NMR spectra of the crude reac-tion mixtures. A very minor amount (5%) of the corre-sponding 1,3-diene elimination product was also observed.

Scheme 1. Synthesis of allylic iodides.

With the necessary allylic halides in hand, we investi-gated their potential in FrterSeebach alkylation. Diethyl

(S)-malate (5), prepared in 95% yield by the esterification

www.eurjoc.org 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Eur. J. Org. Chem. 2012, 9951002996

of l-malic acid,[31] was alkylated with allylic halides andtheir saturated counterparts (Table 1). The saturated alkyliodides were prepared by the iodination of the correspond-ing alcohols or, in the case of iodotetradecane, by the cross-halogenation of bromotetradecane. The overall yields were,in general, similar to those for the preparation of the allyliciodides. In general, the alkylations were performed in THFusing 2.5 equiv. of LDA (generated in situ at 78 C), towhich was added 1 equiv. of 5 followed by 1.5 equiv. of thealkylhalide.

Table 1. The FrterSeebach alkylation using a variety of alkylhalides.

[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 purificationby flash chromatography. [c] Determined by 1H NMR spectro-scopic analysis (in case of the allylic compounds after hydrogena-tion) of the crude reaction mixture.

Our first study involved the alkylation of 5 using eitherallyl bromide (Table 1, Entry 1) or allyl iodide (Table 1, En-try 2) in the absence of hexamethylphosphoramide(HMPA). Both reactions proceeded smoothly to give anti-6a as the predominant diastereomer in respectable yield.Increasing the chain length to C7, however, resulted in 6bin a decreased (37%) yield following purification by flashcolumn 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 reac-tion mixture, 5 decomposed. The use of the C7 allylic iod-ide, 1-iodohept-2-ene (4a), however, resulted in an improved55% yield of the desired -alkylated -hydroxy ester withan anti/syn diastereoselectivity of 9:1 (Table 1, Entry 4).This result was encouraging and demonstrated theimproved reactivity of the allylic system.

The FrterSeebach alkylation was then attempted usingthe C14 homologous (Table 1, Entries 59). When 1-iodote-tradecane was used as the electrophile, a very poor yield ofthe corresponding -alkylated ester 6d was observed(Table 1, Entry 5). A change to 1-bromotetradecane faredno 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. HMPAhas been shown to enhance SN2 reactions by its ability tostrongly solvate cations[32] and has been used by Utaka etal.[33] and Fujisawa et al.[34] to perform -alkylations using1-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 thecorresponding C14 allylic iodide. In the absence of HMPA,the use of 1-iodotetradec-2-ene (Table 1, Entry 8) gave animproved 51% yield of 6e (cf. Table 1, Entry 5). Surpris-ingly, 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 andthe lack of improvement in reaction yield, HMPA was notused in subsequent allylic alkylations.

The difficulties to obtain good yields when using long-chain alkyl iodides in the FrterSeebach alkylation wasfurther demonstrated when attempts were made to alkylate5 using 1-iodoeicosane (Table 1, Entry 10). In our hands,this reaction resulted in a dismal 5% yield. The generalproblem we encountered when performing this -alkylationwas that the reaction was very slow and required the grad-ual warming of the reaction mixture from 78 to 0 C forany product formation to be observed by TLC. Unfortu-nately, the temperature at which the reaction commenced(ca. 20 C) was also the temperature at which 5 began todecompose. Many changes to the solvent, reaction time andequivalents of reagents were then made in an attempt toimprove this yield without success. A change to iodoeicos-2-ene, however, gave the desired -alkylated esters 6g in

49% yield (Table 1, Entry 11). Although some decomposi-tion of5 was observed, we were satisfied with the final yieldofanti-6g given the difficulty of this -alkylation. Attemptsto perform the FrterSeebach alkylation using 1-iododo-cosane gave a mere 8% yield of 6h (Table 1, Entry 12),whereas the use of iododocos-2-ene as an electrophile im-proved the yield to 42% (Table 1, Entry 13). The methodol-ogy was then used to synthesise anti-6j, which contains themost common mycolic acid side chain. Gratifyingly, theyield for this reaction was a respectable 41% (Table 1, En-try 14). This result was particularly pertinent given that thesynthesis of the corresponding linear C24 alkyl iodide takesthree steps, which commences with bromododecanol.[16] In

all examples, the diastereoselectivity of the allylic alkyl-

Eur. J. Org. Chem. 2012, 9951002 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org 997

ations was excellent (ca. 9:1, anti/syn) and was higher thanthose observed for the corresponding saturated alkyl hal-ides.

Having demonstrated the benefit of allylic halides in theFrterSeebach alkylation, we hydrogenated the ,-unsat-urated esters. The mixtures of diastereomers 6 (n = 3, 10,16, 18, 20) were thus hydrogenated in the presence of cata-lytic Pd (5 wt.-%, Scheme 2). Following hydrogenation, thediastereomers were separated by flash column chromatog-raphy 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 (9091%). The excellent yields for the hydrogenation in combi-nation with the significantly improved yields for the allylicalkylation reaction thus demonstrate the potential of ourreaction methodology for the synthesis of long-chain -alk-ylated -hydroxy esters. The esters, in turn, are valuableintermediates en route to the synthesis of the immunomod-ulatory mycolic acids and derivatives thereof.[1723,35] For

example, diester 6b was selectively reduced by treatmentwith BH3DMS[36] to give diol 7, a versatile building blockfor the synthesis of lipophilic hydroxy acids.[37]

Scheme 2. Hydrogenation of the unsaturated diesters.

Finally, to confirm that the allylic alkylations give thesame major diastereomer as that observed when using satu-

rated alkyl halides, a Grubbs cross-metathesis reaction[38]was performed between anti-6a (of known 2S,3R stereo-chemistry)[39] and 1-tridecene to give the saturated esteranti-6e in 41% yield and an E/Z ratio of 4:1 (Scheme 3). Inaddition, the homodimerisation product of 1-tridecene wasobserved along with unreacted allylic ester anti-6a, whichaccounted for the remainder of the material. Hydrogenationof anti-6e then gave a product that exhibited spectroscopicdata consistent with those obtained from the direct alkyl-ation of5 with 1-iodotetradecane (Table 1). This unequivo-cally established that the major isomer from the allylicalkylation was the anticipated 2S,3R-ester.

Scheme 3. Confirming the stereochemistry of the alkylation prod-ucts.

To explain the preferential formation of the 2S,3R dia-stereomer, the rigid cyclic intermediate that is formed dur-ing the course of the reaction needs to be considered(Scheme 4). During the alkylation, more than two equiva-

lents of LDA are added to the -hydroxy ester. One equiva-

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lent is used to deprotonate the hydroxy group, which resultsin the formation of a monoanion where the negativelycharged oxygen is countered by the lithium cation, and thesecond equivalent of LDA leads to the formation of an es-ter enolate in which the lithium cation bridges the two nega-tive charges via a six-membered cyclic intermediate. Regen-eration of the carbonyl group then allows the enolate toattack the alkyl halide, RX, at the face opposite to theester, which is adjacent to the -hydroxy substituent dueto steric hindrance.[15] It also should be noted that greaterreactivity of the allylic system leads to higher diastereoselec-tivity due to the ability of the reactions to be performed atlower temperatures.

Scheme 4. Explanation of the stereoselectivity.

Conclusions

We have developed an improved methodology for thesynthesis of long-chain -alkylated -hydroxy esters by theuse of allylic halides in the FrterSeebach alkylation. This

allylic alkylation is highly diastereoselective and, when com-pared to similar reactions using the corresponding satu-rated alkyl halides, gives superior yields. The prerequisiteallylic iodides were readily prepared in two steps in goodyield from the corresponding aldehydes, and the unsatu-rated -alkylated -hydroxy esters were readily hydroge-nated in excellent yield. The final -alkylated -hydroxy es-ters are, in turn, valuable synthetic intermediates for thepreparation of a number of biologically important lipids.

Experimental Section

General Methods: Unless stated otherwise all reactions were per-formed under an atmosphere of N2. Prior to use, THF was distilledfrom Na wire and benzophenone, toluene was dried and storedwith Na wire, CH2Cl2 was distilled from P2O5 and acetone wasdried with K2CO3, distilled and stored over 4 MS. HMPA wasdried with CaH2, distilled and stored under nitrogen, diisopropyl-amine was dried with NaOH, distilled and stored under nitrogenand allyl bromide, allyl iodide and heptyl iodide were dried withMgSO4, distilled and stored under nitrogen. l-()-Malic acid(Sigma), bromotetradecane (Fluka), 1-docosanol (Aldrich), 1-eicos-anol (Alfa Aesar), 1 m vinylmagnesium bromide (Aldrich), pentan-al (Koch-Light Laboratories), dodecanal (Aldrich), octadecanol(BDH), PPh3 (Merck), I2 (Unilab), Pd/C (Aldrich), H2SO4 (Lab-Scan), ethanol (Pure Science), anhydrous Et2O (Biolab), EtOAc

(EA, Pancreac), petroleum ether (PE, Pure Science), CHCl3


(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 removedby evaporation at reduced pressure. Reactions were monitored byTLC 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. Columnchromatography was performed using Pure Science silica gel (4063 m). HRMS were recorded with a Waters Q-TOF Premier Tan-dem Mass Spectrometer using positive electrospray ionisation. Op-tical rotations were recorded with a PerkinElmer 241 polarimeteror Autopol II instrument (Rudolph Research Analytical) at 589 nm(sodium D-line). IR were recorded as thin films with a Bruker Ten-sor 27 FTIR spectrometer equipped with an attenuated total reflec-tance (ATR) sampling accessory. NMR spectra were recorded at20 C in CDCl3 with a Varian INOVA spectrometer operating at500 MHz. Chemical shifts are given in ppm () relative to TMS.NMR peak assignments were made using COSY, heteronuclear sin-gle quantum coherence and HMBC 2D experiments.

General Procedure for the Synthesis of Allylic Iodides: To a solutionof aldehyde (10 mmol, 1.0 equiv.) in dry THF (50 mL) was addedvinylmagnesium bromide (1 m in THF, 15 mmol, 1.5 equiv.) drop-wise at 0 C. For longer lipids 4ce, freshly prepared vinylmagne-sium bromide was used and the aldehyde was dissolved in tolueneinstead of THF. The mixture was stirred for 90 min at 0 C and 1 hat room temperature. The reaction was quenched by the addition ofNH4Cl, extracted into Et2O (350 mL), and the combined organiclayers were dried with MgSO4, filtered, and concentrated in vacuoto give the allylic alcohol as a viscous oil, which was used withoutfurther purification. To a solution of PPh3 (15 mmol, 1.5 equiv.) inCH2Cl2 (15 mL) was added iodine (15 mmol, 1.5 equiv.), and themixture stirred at room temperature for 5 min. A solution of thecrude allylic alcohol (10 mmol, 1 equiv.) in CH2Cl2 (30 mL) wasadded, and the mixture stirred at room temp. overnight. The reac-tion mixture was diluted with Et2O and washed with saturatedNa2S2O3 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 concentratedin vacuo. Purification of the crude residue by silica gel flash columnchromatography (PE) afforded the allylic iodide.

1-Iodohept-2-ene (4a): By subjecting pentanal (10.0 g, 116 mmol) tothe general procedure for the synthesis of allylic iodides, 4a wasobtained (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 4b-

H), 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 allyliciodides, 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), 3.903.88 (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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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; found323.1242.

1-Iodoeicos-2-ene (4c): By subjecting octadecanal (1.69 g,6.32 mmol) to the general procedure for the synthesis of allyliciodides, 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 4b-H), 1.441.22 (m, 30 H, 5-H19-H), 0.89 (t, J6,7 = 6.7 Hz, 3 H, 20-CH3) 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; found407.2168.

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 wasobtained (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, CDCl

3): = 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. 13CNMR (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; found435.2494.

1-Iodotetracos-2-ene (4e): By subjecting docosanal (3.50 g,10.8 mmol) to the general procedure for the synthesis of allyliciodides, 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 4b-H), 1.371.26 (m, 38 H, 5-H23-H), 0.89 (t, J6,7 = 7.1 Hz, 3 H, 24-CH3) 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 Dies-

ters: nBuLi (2.0 m in hexanes, 11.5 mL, 23.0 mmol) was added to asolution 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 mixturewas stirred at 78 C for 1 h, warmed to 20 C over 1 h and stirredat 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, andthe reaction was stirred for 1 h at 50 C and a further 1 h duringwhich time the temperature increased to 20 C. The reaction wasthen quenched with saturated NH4Cl solution and extracted withEtOAc (3100 mL). The combined organic layers were washedwith water (30 mL) and brine (30 mL), dried (MgSO4), filtered, andthe solvent was removed in vacuo to yield a yellow oil. Purificationof the residue using silica gel flash column chromatography gavethe alkylated product.

Ethyl (2S)-Hydroxy-(3R)-ethoxycarbonylhex-4-enoate (anti-6a): Bythe 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 synthesisof-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 =


14:1). Rf = 0.39 (PE/EA, 2:1, v/v). []D23 = +13.0 (c = 2.23, CHCl3),Ref.[34] []D20 = +11.3 (c = 2.23, CHCl3). IR (film): = 3079, 2982,2961, 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, 3-

CO2CH2), 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 (C-3), 32.2 (C-4), 14.1 (CH3, OEt-1), 14.1 (CH3, CO2Et-3) ppm.HRMS (ESI): calcd. for C11H18O5Na [M + Na]+ 253.1052; found253.1055.

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 thesynthesis of-alkenyl--hydroxy diesters, 6c was obtained (elutingin 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). []D23 = +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, 1-CH2O 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, 4b-H), 2.01 (q, J6,7 = J7,8 = 6.6 Hz, 2 H, 7-H), 1.331.27 (m, 4 H, 8-H 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 (C-1), 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 (C-7), 31.1 (C-8), 22.2 (C-9), 14.2 (C-10), 14.1 (CH

3, 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 (anti-

6e): By the reaction of 5 (3.99 g, 21.0 mmol) with 1-iodotetradec-2-ene (10.14 g, 31.5 mmol) according to the general procedure forthe synthesis of-alkenyl--hydroxy diesters, 6e was obtained (elut-ing 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). []D23 = +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 and2-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, 2H, 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 (C-4), 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 syn-

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thesis of-alkenyl--hydroxy diesters, 6g was obtained (eluting in15:1, 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). []D22 = +6.0 (c = 1.0, CHCl3).IR (film): = 3517, 2924, 2853, 1737, 1219, 1032, 970, 772 cm1.1H 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 2CH3), 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 (C-3), 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 (anti-

6i): By the reaction of 5 (0.53 g, 2.77 mmol) with 1-iododocos-2-

ene (1.80 g, 4.15 mmol) according to the general procedure for thesynthesis of-alkenyl--hydroxy diesters, 6i was obtained (elutingin 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). []D23 = +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 and2-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, 2H, 7a,b-H), 1.331.21 (m, 40 H, 8-H24-H and 2 CH 3), 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 (C-4), 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 (anti-

6j): By the reaction of5 (0.55 g, 2.89 mmol) with 1-iodotetracos-2-ene (2.0 g, 4.32 mmol) according to the general procedure for thesynthesis of-alkenyl--hydroxy diesters, 6j was obtained (elutingin 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). []D22 = +0.1 (c = 1.0,CHCl3). IR (film): = 3351, 2922, 2852, 1736, 1376, 1215, 1042,

756 cm1

.1

H 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 and2-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, 2H, 7a,b-H), 1.371.18 (m, 44 H, 8-H26-H and 2 CH 3), 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 (C-4), 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.


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 solu-tion of diisoproplyamine (6.3 mL, 25.0 mmol) in THF (20 mL) at0 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 wasstirred 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 thereaction stirred for 2 h, during which time the temperature in-creased to 0 C, and stirred for a further 2 h at room temperature.The reaction was quenched using saturated NH4Cl solution andextracted with EtOAc (3100 mL). The combined organic layerswere washed with water (30 mL) and brine (30 mL), dried(MgSO4), filtered, and the solvent was removed in vacuo to yielda yellow oil. Purification of the residue by flash column chromatog-raphy gave the alkylated product.

Ethyl (2S)-Hydroxy-(3R)-ethoxycarbonyldecanoate (anti-6b): By thereaction 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). []D23 = +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, 1-CH2O 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 syn-thesis of -alkyl--hydroxy diesters, 6d was obtained (eluting in15:1, 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). []D23 = +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, 3H, 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): Bythe 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, 6fwas 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). []D23 = +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 2-

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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, 3H, 23-CH3) 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,

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. forC28H54O5Na [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 syn-thesis of -alkyl--hydroxy diesters, 6h was obtained (eluting in15:1, 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). []D22 = +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, 1-CH2O 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, 4b-H), 1.401.24 (m, 46 H, 5-H24-H, 2 CH3), 0.89 (t, J = 6.6 Hz, 3H, 25-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), 29.7, 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 toa solution of the allylic alkylated diester (1 mmol) in a mixture ofCH2Cl2/EtOH (10 mL, 1:1, v/v) and stirred at room temperatureunder H2 overnight. The reaction mixture was filtered through Ce-

lite, the Celite was washed thoroughly with CH2Cl2/EtOH (20 mL,1:1, v/v), and the filtrate was concentrated in vacuo. The productwas purified by flash chromatography.

Ethyl (2S)-Hydroxy-(3R)-ethoxycarbonyldecanoate (anti-6b): Bysubjecting 6c (anti/syn = 9:1, 2.01 g, 6.99 mmol) to the general pro-cedure for hydrogenation, pure anti- 6b was obtained (eluting in15:1 PE/EA, v/v) as a colourless oil (1.81 g, 6.29 mmol, 90%). Thespectroscopic 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 generalprocedure for hydrogenation, pure anti-6d was obtained (eluting in15:1, PE/EA, v/v) as a colourless oil (3.29 g, 8.52 mmol, 91%). Thespectroscopic data matched those reported earlier.

Ethyl (2S)-Hydroxy-(3R)-ethoxycarbonyltricosanoate (anti-6f): Bysubjecting 6g (anti/syn = 9:1, 0.40 g, 0.85 mmol) to the general pro-cedure for hydrogenation, pure anti-6f was obtained (eluting in15:1, PE/EA, v/v) as a white solid (0.36 g, 0.77 mmol, 90%). Thespectroscopic 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 generalprocedure for hydrogenation, pure anti-6h was obtained (eluting in15:1, PE/EA, v/v) as a white solid (0.72 g, 1.45 mmol, 90%). Thespectroscopic 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 generalprocedure 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 =


0.54 (PE/EA, 2:1, v/v). []22D = +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, 2-OH), 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, CO2CH2-3), 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-1and 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 sec-ond-generation catalyst (0.02 g, 0.023 mmol) followed by 1-tride-cene (0.11 mL, 0.46 mmol), and the reaction mixture was heated toreflux under nitrogen for 14 h before being cooled and reduced invacuo. The resulting crude product was purified by column

chromatography to yield anti-6e (eluting in 15:1, PE/EA, v/v) as acolourless oil (0.07 g, 0.19 mmol, 41%). Subsequent hydrogenationof anti-6e according to the above procedure yielded pure anti-6d(0.07 g, 0.18 mmol, 99 %) as a colourless oil. The spectroscopic datamatched those reported above.

(2S)-Hydroxy-(3R)-ethoxycarbonyldecanol (7): Borane dimethyl-sulfide complex (1 m in THF, 0.93 mL, 0.93 mmol) was slowlyadded 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 Cand stirred for 10 min. NaBH4 (0.002 g, 0.04 mmol) was added,and the reaction was warmed to room temperature overnight beforebeing quenched with Dowex H+ (10% by weight) and ethanol(3 mL). The reaction mixture was filtered, washed (EtOH) and con-

centrated in vacuo. The residue was dissolved in toluene/ethanol(1:1, 5 mL) and concentrated (repeated 3) in order to remove eth-anol and boron as B(OEt)3. The resulting crude oil was purified byflash column chromatography (eluting in 3:1, PE/EA, v/v) to give7 as a colourless oil (0.12 g, 0.51 mmol, 60%). Rf = 0.41 (PE/EA,1:1, v/v). []D20 = 11.0 (c = 0.1, CHCl3). 1H NMR (500 MHz,CDCl3): = 4.20 (q, J = 6.8 Hz, 2 H, 3-CO2CH2), 3.843.83 (m, 2H, 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 (CO2-3), 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 arti-cle): Characterisation data and copies of the 1H NMR and 13CNMR spectra.

Acknowledgments

The authors would like to thank the Lotteries Health ResearchGrant 2010 (BLS, MSMT) for financial assistance.

[1] C. H. Heathcock, J. C. Kath, R. B. Ruggeri, J. Org. Chem.

1995, 60, 11201130.

7/28/2019 995_ftp

8/8


[2] M. Eggen, C. J. Mossman, S. B. Buck, S. K. Nair, L. Bhat,S. M. Ali, E. A. Reiff, T. C. Boge, G. L. E. Georg, J. Org.Chem. 2000, 65, 77927799.

[3] K. Mori, S. Kuwahara, Tetrahedron 1986, 42, 55395544.[4] M. T. Crimmins, E. A. OBryan, Org. Lett. 2010, 12, 4416

4419.[5] S. Raghavan, S. R. Reddy, Tetrahedron Lett. 2004, 45, 5593

5595.

[6] S. Raghavan, K. Rathore, Tetrahedron 2009, 65, 1008310092.[7] T. Uno, H. Watanabe, K. Mori, Tetrahedron 1990, 46, 55635566.

[8] F. Xue, W. Gu, R. B. Silverman, Org. Lett. 2009, 11, 51945197.

[9] J. J.-W. Duan, L. Chen, C.-B. Xue, Z. R. Wasserman, K. D.Hardman, M. B. Covington, R. R. Copeland, E. C. Arner,C. P. Decicco, Bioorg. Med. Chem. Lett. 1999, 9, 14531458.

[10] M. Murakami, K. Hinoue, K. Nakagawa, Y. Monden, Y. Furu-kawa, S. Katsumura, Heterocycles 2001, 54, 7780.

[11] P. Kraft, W. Tochtermann, Tetrahedron 1995, 51, 1087510882.[12] G. Frter, Helv. Chim. Acta 1979, 62, 28252828.[13] G. Frter, U. Mller, W. Gnther, Tetrahedron 1984, 40, 1269

1277.[14] G. Frter, Helv. Chim. Acta 1979, 62, 28292832.[15] D. Seebach, D. Wasmuth, Helv. Chim. Acta 1980, 63, 1, 197

200.[16] J. R. Al Dulayyami, M. S. Baird, E. Roberts, Tetrahedron 2005,

61, 1193911951.[17] J. R. Al Dulayyami, M. S. Baird, E. Roberts, J. Chem. Soc.,

Chem. Commun. 2003, 228229.[18] M. Nishizawa, H. Yamamoto, H. Imagawa, V. Barbier-Chasse-

fire, E. Petit, I. Azuma, D. Papy-Garcia, J. Org. Chem. 2007,72, 16271633.

[19] For reviews on mycolic acids and derivatives thereof see: a)R. N. Rao, L. S. Meena, Biotech. Res. Int. 2011, Article ID274693; b) J. M. H. Cheng, A. A. Khan, M. S. M. Timmer,B. L. Stocker, Int. J. Carbohydr. Chem. 2011, Article ID 749591;c) D. E. Minnikin, L. Kremer, L. G. Dover, G. S. Besra, Chem.Biol. 2002, 9, 545553; d) R. Ryll, Y. Kumazawa, I. Yano,Microbiol. Immunol. 2001, 45, 801811; e) C. E. Barry, R. E.

Lee, K. Mdluli, A. E. Sampson, B. G. Schroeder, R. A.Slayden, Y. Yuan, Prog. Lipid. Res. 1998, 37, 143179; f) P. J.Brennan, H. Nikaido, Annu. Rev. Biochem. 1995, 64, 2963.

[20] For recent publications, see: a) K. M. Backus, H. I. Boshoff,C. S. Barry, O. Boutureira, M. K. Patel, F. DHooge, S. S. Lee,L. E. Via, K. Tahlan, C. E. Barry III, B. G. Davis, Nat. Chem.Biol. 2011, 7, 228235; b) A. A. Khan, S. H. Chee, R. J.McLaughlin, J. L. Harper, F. Kamena, M. S. M. Timmer, B. L.Stocker, ChemBioChem 2011, 12, 25722576; c) M. Beukes, Y.Lemmer, M. Deysel, J. R. Al Dulayyami, M. S. Baird, G. Koza,M. M. Iglesias, R. R. Rowles, C. Theunissen, J. Grooten, G.Toschi, V. V. Roberts, L. Pilcher, S. V. Wyngaardta, N. Matheb-ula, M. Balogun, A. C. Stoltz, J. A. Verschoor, Chem. Phys.Lipids 2010, 163, 800808; d) K. Werninghaus, A. Babiak, O.Gross, C. Hlscher, H. Dietrich, E. M. Agger, J. Mages, A. Mo-casi, H. Schoenen, K. Finger, F. Nimmerjahn, G. D. Brown, C.


Kirschning, A. Heit, P. Andersen, H. Wagner, J. Ruland, R.Lang, J. Exp. Med. 2009, 206, 8997; e) E. Rafidinarivo, M.Laneelle, H. Montrozier, P. Valero-Guillen, J. Astola, M. Lu-quin, J.-C. Prome, M. Daffe, J. Lipid Res. 2009, 50, 477490;f) E. Layre, A. Collmann, M. Bastian, S. Mariotti, J. Czaplicki,J. Prandi, L. Mori, S. Stenger, G. De Libero, G. Puzo, Chem.Biol. 2009, 16, 8292.

[21] G. Toschi, M. S. Baird, Tetrahedron 2006, 62, 32213227.

[22] J. R. Al Dulayyami, M. S. Baird, E. Roberts, M. Deysel, J. Ver-schoor, Tetrahedron 2007, 63, 25712592.[23] G. Koza, C. Theunissen, J. R. Al Dulayymi, M. S. Baird, Tetra-

hedron 2009, 65, 1021410229.[24] R. M. Magid, Tetrahedron 1980, 36, 19011930.[25] A. J. Kirby, Stereoelectronic Effects, Oxford University Press,

Bath, 1998, ch. 5.[26] A. Alexakis, C. Malan, L. Lea, K. Tissot-Croset, D. Polet, C.

Falciola, Chimia 2006, 60, 124130.[27] E. J. Alvarez-Manzaneda, R. Chahboun, E. Cabrera Torres, E.

Alvarez, R. Alvarez-Manzaneda, A. Haidour, J. M.Ramos Lpez, Tetrahedron Lett. 2005, 46, 37553759.

[28] K. Marukawa, H. Takikawa, K. Mori, Biosci. Biotechnol. Bio-chem. 2001, 65, 305314.

[29] R. C. Fuson, M. T. Mon, J. Org. Chem. 1961, 26, 756758.[30] A. O. King, E. G. Corley, R. K. Anderson, R. D. Larsen, T. R.

Verhoeven, P. J. Reider, J. Org. Chem. 1993, 58, 37313735.[31] P. Wipf, Y. Uto, S. Yoshimura, Chem. Eur. J. 2002, 8, 1670

1686.[32] R. R. Dykstra, Encyclopedia of Reagents for Organic Synthesis:

Hexamethylphosphoric Triamide, John Wiley & Sons, NewYork, 2001.

[33] M. Utaka, H. Higashi, A. J. Takeda, J. Chem. Soc., Chem.Commun. 1987, 13681369.

[34] T. Fujisawa, A. Fujimura, T. Sato, Bull. Chem. Soc. Jpn. 1988,61, 12731279.

[35] A. Liav, H. M. Flowers, M. B. Goren, Carbohydr. Res. 1984,133, 5358.

[36] S. Saito, T. Ishikawa, A. Kuroda, K. Koga, T. Moriwake, Tetra-hedron 1992, 48, 40674086.

[37] For the transformation of diols into hydroxy lipids, see: a) C.

Gravier-Pelletier, Y. L. Merrer, J.-C. Depezay, Tetrahedron1995, 51, 16631674; b) D. K. Mohapatra, D. Bhattasali, M. K.Gurjar, M. I. Khan, K. S. Shashidhara, Eur. J. Org. Chem.2008, 36, 62136224; c) C. L. Morris, Y. Hu, G. D. Head, L. J.Brown, W. G. Whittingham, R. C. D. Brown, J. Org. Chem.2009, 74, 981988; d) A. C. Allepuz, R. Badorrey, M. D. Daz-de-Villegas, J. A. Glvez, Eur. J. Org. Chem. 2009, 61726178.

[38] A. K. Chatterjee, T. Choi, D. P. Sanders, R. H. Grubbs, J. Am.Chem. Soc. 2003, 125, 1136011370.

[39] D. Seebach, J. Aebi, D. Wasmuth, Org. Synth. 1990, 7, 153162.

[40] D. Pijper, E. Bulten, J. Smisterova, A. Wagenaar, D. Hoekstra,J. B. F. N. Engberts, R. Hulst, Eur. J. Org. Chem. 2003, 44064412.

Received: October 10, 2011Published Online: December 16, 2011

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