A practical synthesis of long-chain iso-fatty acids (iso-C₁₂–C₁₉) and related natural products

Abstract

A gram-scale synthesis of terminally-branched iso-fatty acids (iso-C₁₂–C₁₉) was developed commencing with methyl undec-10-enoate (methyl undecylenate) (for iso-C₁₂–C₁₄) or the C₁₅ and C₁₆ lactones pentadecanolide (for iso-C₁₅–C₁₇) and hexadecanolide (for iso-C₁₈–C₁₉). Central to the approaches outlined is the two-step construction of the terminal isopropyl group through addition of methylmagnesium bromide to the ester/lactones and selective reduction of the resulting tertiary alcohols. Thus, the C₁₂, C₁₇ and C₁₈ iso-fatty acids were obtained in three steps from commercially-available starting materials, and the remaining C₁₃–C₁₆ and C₁₉ iso-fatty acids were prepared by homologation or recursive dehomologations of these fatty acids or through intercepting appropriate intermediates. Highlighting the synthetic potential of the iso-fatty acids and various intermediates prepared herein, we describe the synthesis of the natural products (S)-2,15-dimethylpalmitic acid, (S)-2-hydroxy-15-methylpalmitic acid, and 2-oxo-14-methylpentadecane.

Introduction

Long-chain iso-fatty acids occur in a broad range of organisms, and are especially abundant in bacteria where, through incorporation into phospholipids, they influence membrane fluidity [1]. Emerging evidence has revealed unexpected roles for certain iso-fatty acids; for example iso-C₁₅ and iso-C₁₇ fatty acids have been shown to be essential in the development of the model eukaryote Caenorhabditis elegans [2]. They are present as esters and amides in natural products including septacidin [3], teicoplanins [4], tunicaminyluracil-based antibiotics [5] (tunicamycins [6], corynetoxins [7], and streptovirudins [8]), the arylomycin glycopeptide antibiotics [9–10], maradolipids [11], plipastatin-type lipopeptides [12], Nod factors [13], glycosylglycerides [14–15], phosphoglycolipids [16], and various sphingolipids [17–19]. The terminal isopropyl group of the iso-fatty acids arises from valine and leucine, which through transamination and decarboxylation reactions yield isobutyryl-CoA and isovaleryl-CoA [20]. These starter units are elongated by fatty acid synthases to the final iso-fatty acids (even numbered for isobutyryl-CoA; odd-numbered for isovaleryl-CoA) through extension with malonyl-CoA [21–22]. Long-chain iso-fatty acids are important analytical reference compounds owing to the presence of these materials in tobacco [23], wool wax [24], butter fat [25], human sebaceous secretions [26] (adult skin [27], meibum [28], cerumen [29], and newborn vernix caseosa [30–31]), and a wide variety of microbiological samples [1].

Previous syntheses of iso-fatty acids have typically utilized extended, multi-step sequences. Two main approaches have been used: (1) two-component cross-couplings that include α-ketoester alkylation/decarboxylation [32–33], aldehyde–olefin photoaddition [34], acetylide alkylation (sp³–sp) [35–36], Wittig coupling [3,21,37–39], Kolbe electrosynthesis [35,40–42], organocadmium (sp²–sp³) [43–46], organomagnesium (sp²–sp³) [47], or organocopper (sp³–sp³) [48–49] cross-couplings; or (2) bidirectional extension of a central thiophene C₄-fragment [50]. Two fundamentally different approaches worth special mention are the synthesis of the iso-C₁₄ acid 3 by direct hydro-isopropylation of the terminal alkene of methyl undecylenate (available as a pyrolysis product of ricinoleic acid) using isopropyl chloroformate and ethyldichloroaluminium [51], and the synthesis of the iso-C₁₇ acid 6 from methyl ustilate (15,16-dihydroxypalmitate) [52]. Despite the interest in natural products containing iso-fatty acids, these compounds are not readily acquired in multigram quantities due to the complexity of the synthetic routes or limited availability of starting materials. To overcome these problems, we report the scalable, gram-scale syntheses of eight common iso-C₁₂–C₁₉ acids 1–8 (Figure 1), from readily available starting materials. To illustrate the opportunities that our approach provides, we demonstrate the elaboration of the C₁₇-iso-fatty acid 6 and an intermediate, 22, to several terminal-branched natural products that have not previously been synthesized.

Figure 1.

Structures of iso-fatty acids.

Results and Discussion

Our approach to the iso-C₁₂–C₁₄ fatty acids 1–3 commenced from methyl undec-10-enoate (methyl undecylenate) 9. Reaction of 9 with methylmagnesium bromide afforded the tertiary alcohol 10 in 98% yield (Scheme 1). Selective reduction of the tertiary alcohol of 10 was achieved by ‘ionic hydrogenation’ with triethylsilane and BF₃·Et₂O [53], affording 11. Oxidative cleavage of 11 with KMnO₄/Bu₄NBr [54] afforded iso-C₁₂ acid 1. Alternatively, anti-Markovnikov hydration of 11, using I₂/NaBH₄ then hydrogen peroxide [55], afforded the alcohol 12, and oxidation of 12 with KMnO₄/Bu₄NBr afforded iso-C₁₃ acid 2. Alternatively, alcohol 12 could be intercepted and converted to the mesylate 13 using MsCl/Et₃N [56] and thence the nitrile 14 (KCN in DMSO/THF). Finally, hydrolysis of the nitrile 14 with NaOH in H₂O/EtOH afforded iso-C₁₄ acid 3.

Scheme 1.

Synthesis of iso-C₁₂ 1, iso-C₁₃ 2, and iso-C₁₄ 3 fatty acids from methyl undecylenate (9). Reagents and conditions: (a) MeMgBr, THF, 98%; (b) BF₃·Et₂O, Et₃SiH, CH₂Cl₂, 99%; (c) KMnO₄, Bu₄NBr, AcOH, H₂O, 88% for 1, 96% for 2; (d) i) I₂, NaBH₄, THF, ii) H₂O₂, 95%; (e) MsCl, Et₃N, CH₂Cl₂, 98%; (f) KCN, DMSO, THF, 72%; (g) aq NaOH, EtOH, 96%.

The iso-C₁₅–C₁₇ fatty acids 4–6 were prepared from the readily available C₁₅ lactone pentadecanolide (exaltolide, 15) [57], a natural product that is produced industrially for use as a musk-odored perfumery fixative. Reaction of 15 with methylmagnesium bromide afforded the tertiary alcohol 16 in 98% yield (Scheme 2). Selective reduction of the tertiary alcohol of 16 was achieved using triethylsilane/BF₃·Et₂O [53], yielding 17. Finally, oxidation of 17 with KMnO₄/Bu₄NBr [54] afforded the iso-C₁₇ acid 6. The iso-C₁₅ acid 4 and iso-C₁₆ acid 5 were prepared by recursive dehomologation through intercepting the alcohol 17. Preparation of the xanthate ester 18 (NaH, CS₂, then MeI) [58] followed by Chugaev elimination afforded the terminal alkene 19. Oxidative cleavage of 19 using KMnO₄/Bu₄NBr [54] afforded iso-C₁₆ acid 5. Reduction of 5 (BH₃·Me₂S) [59] afforded the alcohol 20 that when subjected to the same transformations as before, via the xanthate ester 21, delivered the terminal alkene 22. Finally, oxidative cleavage (KMnO₄/Bu₄NBr) [54] of 22 afforded iso-C₁₅ acid 4.

Scheme 2.

Synthesis of iso-C₁₅ 4, iso-C₁₆ 5, and iso-C₁₇ 6 fatty acids from pentadecanolide (15). Reagents and conditions: (a) MeMgBr, THF, 98%; (b) BF₃·Et₂O, Et₃SiH, CH₂Cl₂, 96%; (c) KMnO₄, Bu₄NBr, AcOH, H₂O, 95% for 6, 93% for 5; 86% for 4; (d) NaH, CS₂ then MeI; (e) reflux, 89% for 19 over 2 steps from 17, 98% for 22 over 2 steps from 20; (f) BH₃·SMe₂, THF, 78%.

The iso-C₁₈ 7 and iso-C₁₉ 8 fatty acids were synthesized through similar approaches from the related C₁₆ lactone hexadecanolide 23 [60] (Scheme 3). Reaction of 23 with methylmagnesium bromide afforded 24; triethylsilane/BF₃·Et₂O [53] reduction gave 25; and KMnO₄/Bu₄NBr oxidation afforded iso-C₁₈ acid 7 (Scheme 3). The iso-C₁₉ acid 8 was readily prepared by a three-step homologation through intercepting the alcohol 25. Thus, mesylation of 25 (MsCl/Et₃N [56]) afforded 26; substitution (KCN/DMSO) afforded the nitrile 27; and hydrolysis (NaOH in H₂O/EtOH) of 27 afforded 8.

Scheme 3.

Synthesis of iso-C₁₈ 7 and iso-C₁₉ 8 fatty acids from hexadecanolide 23. Reagents and conditions: (a) MeMgBr, THF, 97%; (b) BF₃·Et₂O, Et₃SiH, CH₂Cl₂, 95%; (c) KMnO₄, Bu₄NBr, AcOH, H₂O, 82%; (d) MsCl, Et₃N, 96%; (e) KCN, DMSO, THF, 75%; (f) aq NaOH, EtOH, 86%.

The above routes enable the acquisition of (multi)gram quantities of the iso-C_12–19 acids 1–8, and provide opportunities for their use as starting materials for the preparation of more complex fatty acids. To illustrate their potential we undertook the synthesis of several representative natural products (Scheme 4). 2,15-Dimethylpalmitic acid has been isolated from a microaerophilic subsurface microbial community [61], and is a component of human newborn vernix caseosa [31], although the absolute configuration of natural samples has not been determined. Conversion of iso-C₁₇ acid 6 to the N-acyloxazolidinone 28 was achieved using pivalyl chloride/LiCl [62] and (S)-4-benzyloxazolidinone. Diastereoselective methylation [63] of the chelated Z-enolate, derived from deprotonation of 28, using NaHMDS, followed by addition of iodomethane, yielded 29 as a single diastereoisomer (as determined by ¹H NMR) in 80% yield. Cleavage of the chiral auxiliary using LiOH/H₂O₂ (which occurs without racemization at the α-position) [64] afforded (S)-2,15-dimethylpalmitic acid (30) in 98% yield. 2-Hydroxy-15-methylpalmitic acid has been identified from a range of sources [1] including the myxobacterium Stigmatella aurantiaca [21,65], and the oral bacterium Veillonella parvula [66], although the absolute configuration has not been reported. Diastereoselective hydroxylation [67] of the chelated Z-enolate derived from 28 using the Davis oxaziridine [68] afforded the 2-hydroxy compound 31 as a single diastereoisomer (as determined by ¹H NMR) in 71% yield. Esterification with MeOMgCl [69] (which has been shown not to cause epimerization at the α-position [67]) and saponification [70] afforded (S)-2-hydroxy-15-methylpalmitic acid (32). The ketone 33 was isolated from Xanthomonas campestris pv. vesicatoria 85-10 [71]. A direct one step synthesis of 33 was achieved in 51% yield by Wacker oxidation using Pd/O₂ [72] of the alkene 22, intercepted from the synthesis of the iso-C₁₅ acid 4.

Scheme 4.

Synthesis of (A) 2-methyl- and 2-hydroxy-iso-fatty acids 30 and 32, and (B) the ketone 33. Reagents and conditions: (a) Et₃N, PivCl, LiCl, DMAP, (S)-4-benzyloxazolidinone, 71%; (b) NaHMDS, MeI, THF, 80%; (c) LiOH, H₂O₂, THF, H₂O, 98%; (d) NaHMDS, Davis oxaziridine, THF, 71%; (e) i) iPrMgCl, MeOH, 76%, ii) NaOH, MeOH, 83%; (f) O₂, PdCl₂, DMA, H₂O, 51%.

Conclusion

We have accomplished a highly practical synthesis of the homologous iso-fatty acids 1–8. The iso-C₁₂ 1, iso-C₁₇ 6 and iso-C₁₈ 7 acids were prepared from commercially-available starting materials through three-step sequences and produced more than 1 g of each of the three iso-fatty acids in just 2 days each. The remaining five fatty acids were each prepared on >1 g scale by homologation or dehomologation reactions, or through the elaboration of intermediates in the synthesis of 1. Underscoring the practicability of this approach, the iso-fatty acids or appropriate intermediates were used for the preparation of three natural products, enantiopure acids 30 and 32, and the ketone 33. The simplicity of our approach suggests that it will be of great utility in the preparation of iso-fatty acids for incorporation into more complex molecules.

Supporting Information

File 1

Experimental part.

File 2

NMR spectra.