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Synlett 2023; 34(18): 2159-2164
DOI: 10.1055/a-2077-2113
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Modern Boron Chemistry: 60 Years of the Matteson Reaction

A Straightforward Synthesis of Emericellamide A Using Matteson’s Homologation Approach

Ronja Priester
,
Uli Kazmaier  ∗

Financial support from Saarland University and the DFG (Grants: Ka 880/13-1; Bruker Neo 500 - 447298507) is gratefully acknowledged
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Abstract

The Matteson homologation is the perfect approach for the synthesis of polyketide–peptide natural products such as the emericellamides. In only four steps, the polyketide fragment with three stereogenic centers can be obtained as a single stereoisomer. The peptide fragment is easily available via solid-phase peptide synthesis.


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Key words

boronic esters - Matteson homologation - natural products - peptides - stereoselective synthesis

Emericellamide A and B are two cyclic lipopeptides that were isolated from the marine-derived fungus Emericella sp. by Fenical et al. in 2007 (Figure [1]). These natural products are produced in such tiny amounts that they were not detectable by standard LC-MS techniques. Their rate of production could be increased 100-fold, however, if the fungus was co-cultured in the presence of the marine actinomycete Salinospora arenicola.[1] Biosynthetically, the peptide fragment is formed by a non-ribosomal peptide synthetase (NRPS), while the β-hydroxycarboxylic acid is the result of a polyketide synthase (PKS). A year later, in 2008, emericellamide A was also isolated from Aspergillus nidulans.[2] Gene-targeting techniques have enabled the identification of the specific genes involved in the biosynthesis of these compounds, as well as the discovery of new derivatives, emericellamide C–F, which primarily differ in the methylation pattern and length of the carboxylic acid chain.[2]

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Figure 1 Emericellamide A and B

First biological studies indicated that emericellamides A and B show activity against methicillin-resistant Staphylococcus aureus (MRSA) strains in the low-μM range [MIC: 3.8. μM (A), 6.0 μM (B)], as well as moderate cytotoxicity against HCT-116 cells [IC50: 23 μM (A), 40 μM (B)]. Emericellamide A was found to be the slightly more active compound.[1] No activity was observed towards amphotericin-resistant Candida albicans. Further biological data have not been reported so far.

The low cytotoxicity and observed activity against MRSA have increased the interest of research chemists in developing synthetic routes for these compounds. Currently, six different syntheses for emericellamide A and/or emericellamide B have been reported and differ primarily in the synthesis of the polyketide moiety of the molecules. In most cases, the stereogenic centers of the β-hydroxycarboxylic acid were incorporated using Evans auxiliary chemistry[3] in combination with a Sharpless epoxidation/epoxide opening[4] or allylborations.[5] Ghosh et al. further explored a Paterson anti-aldol reaction,[6] and Yaday et al. utilized the desymmetrization of a bicyclic precursor to generate the polyketide building block.[7] A common feature of all these syntheses is a long linear sequence of at least 10 steps for generating a suitable synthetic building block for the ongoing synthesis.

For the past couple of years, our group has been involved in the total synthesis of natural products with antibiotic[8] or anticancer[9] activity; thus, we have also focused our attention on the emericellamides. Inspired by a 2013 review article by Donald Matteson on his life’s work,[10] we became very interested in this brilliant type of chemistry.[11] [12] In its asymmetric version, the Matteson homologation, which was introduced in the early 1980s, is particularly suited for generating highly substituted and functionalized alkyl chains (Scheme [1]). An α-chloro- or α-bromoboronic ester is formed in the first step by reacting deprotonated dichloro- or dibromomethane with an alkylboronic ester, which can subsequently be reacted with various nucleophiles, such as Grignard reagents or alkoxides, under inversion. The stereochemical outcome of the reaction is solely controlled by the chiral auxiliary in the boronic ester.[13] Therefore, this reaction is perfectly suited for generating polyketide-like structures. It is more flexible than the commonly used aldol reactions because the substituents can be incorporated at almost any position, and not only in a 1,3-manner. Unsurprisingly, several versions of the Matteson homologation have found applications in the total synthesis of natural products.[14]

Zoom Image
Scheme 1 Matteson homologation

Thus, we were also inspired to use the Matteson homologation as a key step in the total synthesis of emericellamide A, as the most potent representative of this class of compounds. Retrosynthetically, emericellamide A can be separated into a peptide and a polyketide fragment, which can subsequently be coupled by esterification followed by macrolactamization.[4]

For the synthesis of tripeptide 4 as the first building block, we used an Fmoc-based solid-phase peptide synthesis (SPPS) (Scheme [2]).[15] Starting from an Fmoc-alanine preloaded polystyrene resin with a Wang-linker, we sequentially coupled the amino acids Fmoc-leucine and Fmoc-valine, using piperidine as a deprotecting reagent and oxyma (ethyl(hydroxyimino)cyanoacetate) and N,N′-diisopropylcarbodiimide (DIC) as coupling reagents. Subsequently, peptide 3 was again Fmoc-deprotected, cleaved from the resin with the cleavage cocktail TFA/TIPS (triisoproylsilane)/H2O, and finally protected with a Boc-group to afford tripeptide 4 in 71% overall yield.

To obtain the second polyketide building block, we synthesized β-hydroxycarboxylic acid 9 via Matteson homologation[16] (Scheme [3]). We started from the known methylboronic ester 5,[17] which was converted into the homologated boronic ester 6 [18] under standard conditions using a hexyl Grignard reagent as a nucleophile. The next homologation was carried out with p-methoxybenzylate to obtain the alkoxyboronic ester 7.[19] In this step, DMSO was added as a cosolvent to accelerate the 1,2-migration of the alkoxy nucleophile.[20] The following introduction of a methyl group proceeded slowly under the usual conditions. However, we were able to halve the reaction time to four days by isolating the α-chloroboronic ester prior to further reaction with the methyl Grignard reagent.[21] A final Matteson homologation provided the corresponding α-chloroboronic ester, which was oxidized to the carboxylic acid 9 under Pinnick conditions.[22] Unfortunately, separation of the product from the chiral auxiliary diol was not possible at this stage. Therefore, the subsequent coupling with glycine benzyl ester was carried out with the crude product and using 1-hydroxybenzotriazole (HOBt) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) as coupling reagents. Following esterification of the chiral auxiliary with methylboronic acid, which regenerated the starting material 5, the amide 10 [23] could be separated and subsequently PMB (p-methoxybenzyl)-deprotected with TFA to afford the corresponding alcohol 11 [24] as a single stereoisomer.

Zoom Image
Scheme 2 Synthesis of the peptide fragment 4. Reagents and conditions: (a) piperidine (20 vol% in DMF); 1. 75 °C, 155 W, 15 s; 2. 90 °C, 30 W, 50 s. (b) Fmoc-Leu-OH (4.0 equiv). (c) DIC (4.0 equiv), Oxyma (4.0 equiv), 1. 75 °C, 170 W, 15 s; 2. 90 °C, 30 W, 110 s. (d) Fmoc-Val-OH (4.0 equiv). (e) TFA/TIPS/H2O (95:2.5:2.5), r.t., 90 min. (f) Boc2O (1.3 equiv), NaHCO3 (2.2 equiv), THF/H2O, r.t., 1 d.
Zoom Image
Scheme 3 Synthesis of emericellamide A. Reagents and conditions: (a) CH2Cl2 (2.5 equiv), nBuLi (1.1 equiv), ZnCl2 (1.1–3.1 equiv), THF, –100 °C to r.t., 5 h. (b) nHexMgCl (2.0 equiv), THF, 0 °C to r.t., 3 d. (c) NaOPMB (1.5 equiv), THF/DMSO, 0 °C to r.t., 1 d. (d) MeMgCl (2.5 equiv), ZnCl2 (1.1 equiv), THF, 0 °C to r.t., 4 d. (e) NaClO2 (10 equiv), KH2PO4 (10 equiv), 2-methyl-2-butene (21 equiv), tBuOH/H2O, r.t., 1 d. (f) H-Gly-OBn·HCl (1.3 equiv), HOBt (1.1 equiv), EDC·HCl (1.1 equiv), DIPEA (2.2 equiv), CH2Cl2, 0 °C to r.t., 1 d. (g) MeB(OH)2 (1.1 equiv), Et2O, r.t., 1 h. (h) TFA (5.0 equiv), CH2Cl2, 0 °C, 30 min. (i) Boc-Ala-OH (2.0 equiv), DCC (1.6 equiv), 4-Pyrrolidinylpyridine (1.2 equiv), CH2Cl2, 0 °C to r.t., 2 h. (k) HCl in dioxane (4 M), CH2Cl2, 0 °C to r.t., 2 h. (l) Boc-Val-Leu-Ala-OH (1.2 equiv), HATU (1.5 equiv), DIPEA (2.0 equiv), CH2Cl2, 0 °C to r.t., 2 h. (m) Pd/C (10%), H2, MeOH, r.t., 2 h. (n) HCl in dioxane (4 M), CH2Cl2, 0 °C to r.t., 90 min. (o) FDPP (1.9 equiv), DIPEA (3.8 equiv), MeCN, 0 °C to r.t., 15 h.

To complete the total synthesis, we planned to couple the polyketide fragment 11 with the tetrapeptide (Boc-Val-Leu-Ala-Ala-OH). We explored many different strategies for the esterification, such as those described by Steglich,[25] Yamaguchi[26] or Ghosez,[27] but without success. This was the rationale we used to first connect the polyketide fragment 11 with Boc-alanine to obtain the ester 12.[28] The optimal result was obtained with N,N′-dicyclohexylcarbodiimide (DCC) and 4-pyrrolidinylpyridine[29] as esterification reagents; however, this approach resulted in an 81:19 diastereomeric mixture. Unfortunately, the diastereomers could not be separated at this stage. Following the acidic cleavage of the Boc-group, the ester 12 was coupled with the previous synthesized tripeptide 4 in the presence of hexafluorophosphate azabenzotriazole tetramethyl uronium (HATU), which afforded compound 13 [30] without any difficulties. At this stage, chromatographic separation of the diastereomers was possible. Finally, cleavage of the benzyl ester by hydrogenation using Pd/C as a catalyst, followed by deprotection of the Boc-group with HCl in dioxane, yielded the free amino acid. After the final macrolactamization with pentafluorophenyl diphenylphosphinate (FDPP)[31] and N,N-diisopropylethylamine (DIPEA) under high dilution,[3] we isolated the natural product emericellamide A[32] in three steps, in a yield of 48%.

In conclusion, we were able to show that the Matteson homologation is the perfect approach for the synthesis of polyketide–peptide natural products such as the emericellamides. In only four steps, the polyketide fragment with three stereogenic centers could be obtained as a single stereoisomer. The peptide fragment was easily available via solid-phase peptide synthesis. Therefore, this approach should also give access to further derivatives for structure–activity relationship (SAR) studies, which are currently under investigation.


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Conflict of Interest

The authors declare no conflict of interest.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-2077-2113.
  • Supporting Information

  • References and Notes

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  • 16 General Procedure (GP): Matteson Homologation In a flame-dried Schlenk tube, a solution of anhydrous dichloromethane (2.5 equiv) in anhydrous THF (2.0 mL/mmol) was cooled to –100 °C and nBuLi (2.5 M in hexane, 1.1 equiv) was added dropwise. After stirring for 30 min at this temperature, boronic ester (1.0 equiv) in anhydrous THF (1.5 mL/mmol) was added slowly and the resulting solution was stirred at –100 °C for a further 30 min. Thereafter, ZnCl2 (1.1–1.3 equiv; flame-dried in vacuo) was dissolved in anhydrous THF (0.8 mL/mmol ZnCl2) and added to the reaction mixture. The solution was stirred for 1 d while warming to room temperature to give the corresponding α-chloroboronic ester. After cooling to 0 °C, nucleophile solution (1.5–2.5 equiv) was added dropwise and the reaction mixture was stirred at room temperature until full conversion. The mixture was then added to a separatory funnel containing saturated NH4Cl-solution and pentane and the phases were separated. The aqueous phase was extracted three times with pentane and the combined organic phases were dried over MgSO4. After removing the solvent in vacuo, the crude product was purified by column chromatography For compounds 8 and 9, the procedure was slightly modified by isolating the α-chloroboronic ester. After the homologation step, the reaction mixture was worked up as described above. For the further conversion, the isolated α-chloroboronic ester and ZnCl2 (1.1 equiv; flame-dried in vacuo) was dissolved in anhydrous THF (4.0 mL/mmol) and cooled to 0 °C. Afterwards, the nucleophile solution (2.5 equiv) was added dropwise and the reaction mixture was stirred at room temperature until full conversion
  • 18 Preparation of Boronic Ester 6: According to the GP,16 methylboronic ester 5 (2.98 g, 11.9 mmol) was stirred with dichloromethane (1.92 mL, 29.8 mmol), nBuLi (5.24 mL, 13.1 mmol), ZnCl2 (1.79 g, 13.1 mmol) and HexMgCl (11.9 mL, 23.8 mmol, 2.0 M in THF) for 3 d. After purification by column chromatography (silica, pentane/Et2O 99:1), the boronic ester 6 (3.20 g, 9.17 mmol, 77%) was obtained as a colorless oil. Rf (6) = 0.60 (silica, pentane/Et2O 97:3). [α]D 20 –37.8 (c = 1.0, CHCl3). 1H NMR (CDCl3, 500 MHz): δ = 0.87 (t, J = 6.9 Hz, 3 H), 0.91–1.00 (m, 2 H), 0.97 (d, J = 7.3 Hz, 3 H), 1.02–1.08 (m, 2 H), 1.10–1.23 (m, 6 H), 1.23–1.34 (m, 12 H), 1.40–1.47 (m, 1 H), 1.57–1.60 (m, 2 H), 1.66–1.68 (m, 2 H), 1.75–1.77 (m, 6 H), 3.81–3.84 (m, 2 H). 13C NMR (CDCl3, 125 MHz): δ = 14.1, 15.8, 22.6, 25.9, 26.0, 26.5, 27.4, 28.2, 28.9, 29.5, 31.9, 33.4, 43.1, 83.1. HRMS (CI): m/z [M + H]+ calcd for C22H42 11BO2 +: 349.3272; found: 349.3281.
  • 19 Preparation of Boronic Ester 7: According to the GP,16 boronic ester 6 (1.71 g, 4.91 mmol) was stirred with dichloromethane (790 μL, 12.3 mmol), nBuLi (2.16 mL, 5.40 mmol) and ZnCl2 (736 mg, 5.40 mmol). The nucleophile solution was prepared by adding (4-methoxyphenyl)methanol (975 μL, 7.85 mmol) to a suspension of NaH (294 mg, 7.36 mmol, 60% in mineral oil) in anhydrous DMSO (10.7 mL) and anhydrous THF (2.7 mL). After addition of the nucleophile solution, the reaction mixture was stirred for 1 d. The crude product was purified by column chromatography (silica, pentane/Et2O 95:5) to give the boronic ester 7 (2.11 g, 4.22 mmol, 86%) as a colorless oil. Rf (7) = 0.63 (silica, pentane/Et2O 9:1). [α]D 20 –16.2 (c = 1.0, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 0.87 (t, J = 7.3 Hz, 3 H), 0.94 (d, J = 6.9 Hz, 3 H), 0.95–1.02 (m, 2 H), 1.04–1.10 (m, 3 H), 1.13–1.34 (m, 16 H), 1.43–1.50 (m, 1 H), 1.58–1.61 (m, 2 H), 1.67–1.69 (m, 2 H), 1.75–1.81 (m, 5 H), 3.11 (d, J = 6.0 Hz, 1 H), 3.80 (s, 3 H), 3.88–3.90 (m, 2 H), 4.36–4.54 (m, 2 H), 6.84–6.86 (m, 2 H), 7.26–7.27 (m, 2 H). 13C NMR (125 MHz, CDCl3): δ = 14.1, 16.9, 22.7, 25.9, 26.0, 26.4, 27.5, 27.6, 28.4, 29.6, 31.9, 33.8, 35.4, 43.0, 55.2, 72.2, 83.6, 113.5, 129.3, 131.5, 158.9. HRMS (CI): m/z [M–H]+ calcd for C31H50 11BO4 +: 497.3802; found: 497.3785.
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  • 21 Preparation of Boronic Ester 8: According to the modified GP,16 boronic ester 7 (1.36 g, 2.73 mmol) was stirred with dichloromethane (439 μL, 6.82 mmol), nBuLi (1.20 mL, 3.00 mmol), ZnCl2 (1.15 g, 8.46 mmol) and MeMgCl (2.27 mL, 6.82 mmol, 3 M in Et2O) for 4 d. After purification by column chromatography (silica, pentane/Et2O 97:3), boronic ester 8 (1.15 g, 2.18 mmol, 80%) was obtained as a colorless oil. Rf (8) = 0.31 (silica, pentane/Et2O 95:5). [α]D 20 –28.4 (c = 1.0, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 0.88 (t, J = 6.9 Hz, 3 H), 0.91 (d, J = 6.6 Hz, 3 H), 0.99 (d, J = 7.6 Hz, 3 H), 0.94–1.03 (m, 4 H), 1.08–1.34 (m, 18 H), 1.55–1.57 (m, 3 H), 1.63–1.67 (m, 2 H), 1.71–1.73 (m, 5 H), 1.79–1.81 (m, 2 H), 3.31 (t, J = 5.7 Hz, 1 H), 3.77–3.79 (m, 2 H), 3.79 (s, 3 H), 4.42–4.57 (m, 2 H), 6.84–6.86 (m, 2 H), 7.25–7.27 (m, 2 H). 13C NMR (125 MHz, CDCl3): δ = 11.8, 14.1, 15.2, 22.7, 25.9, 26.0, 26.4, 27.6, 27.8, 28.5, 29.6, 32.0, 33.8, 35.9, 43.0, 55.3, 72.0, 83.4, 86.2, 113.5, 128.7, 131.8, 158.7. HRMS (CI): m/z [M–H]+ calcd for C33H54 11BO4 +: 525.4120; found: 525.4125.
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  • 23 Preparation of Amide 10: According to the modified GP,16 boronic ester 8 (2.12 g, 4.03 mmol) was stirred with dichloromethane (648 μL, 10.1 mmol), nBuLi (1.77 mL, 4.43 mmol), and ZnCl2 (1.70 g, 12.5 mmol) to give the corresponding α-chloroboronic ester (2.30 g, 4.00 mmol). The crude product was dissolved in tBuOH (35 mL) and 2-methyl-2-butene (9.00 mL, 84.9 mmol) was added. A solution of NaClO2 (4.56 g, 40.3 mmol, 80%) and KH2PO4 (5.48 g, 40.3 mmol) in H2O (35 mL) was added and the reaction mixture was stirred at room temperature for 1 d. Thereafter, the reaction solution was acidified with citric acid (10 vol%) and the aqueous phase was extracted three times with Et2O. The combined organic phases were washed with saturated Na2S2O3-solution, dried over MgSO4 and concentrated under reduced pressure to give a mixture of the carboxylic acid 9 and the chiral auxiliary (2.02 g) as a yellow oil without further purification. The mixture was then dissolved in anhydrous dichloromethane (20 mL) and H-Gly-OBn∙HCl (1.06 g, 5.24 mmol) was added. After cooling to 0 °C, DIPEA (1.55 mL, 8.87 mmol), HOBt (679 mg, 4.43 mmol) and EDC∙HCl (850 mg, 4.43 mmol) were added and the reaction solution was stirred at room temperature overnight. The solvent was removed in vacuo and the residue redissolved in ethyl acetate. The solution was washed with KHSO4 solution (1 M), saturated NaHCO3 solution, and saturated NaCl solution, the organic phase was dried over MgSO4 and concentrated under reduced pressure. The residue was dissolved in Et2O (15 mL) and methylboronic acid (265 mg, 4.43 mmol) was added. After stirring for 1 h, the solvent was removed in vacuo and the product was purified by column chromatography (silica, pentane/ethyl acetate 75:25) to give the amide 10 (1.33 g, 2.74 mmol, 68% over two steps) as a colorless oil. Rf (10) = 0.42 (silica, pentane/ethyl acetate 7:3). [α]D 20 –7.5 (c = 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 0.88 (t, J = 6.7 Hz, 3 H), 0.91 (d, J = 6.7 Hz, 3 H), 1.15 (d, J = 7.0 Hz, 3 H), 1.22–1.31 (m, 9 H), 1.41–1.48 (m, 1 H), 1.68–1.73 (m, 1 H), 2.53 (quint, J = 7.1 Hz, 1 H), 3.47 (dd, J = 7.2, 4.0 Hz, 1 H), 3.78 (s, 3 H), 3.88 (dd, J = 18.3, 4.7 Hz, 1 H), 4.15 (dd, J = 18.3, 5.8 Hz, 1 H), 4.45–4.53 (m, 2 H), 5.15 (s, 2 H), 6.55 (t, J = 5.0 Hz, 1 H), 6.82–6.85 (m, 2 H), 7.21–7.24 (m, 2 H), 7.31–7.38 (m, 5 H). 13C NMR (100 MHz, CDCl3): δ = 14.0, 14.1, 15.7, 22.7, 27.3, 29.5, 31.9, 34.1, 35.5, 41.3, 44.5, 55.2, 67.0, 74.9, 85.0, 113.7, 128.3, 128.5, 128.6, 129.2, 130.9, 135.3, 159.1, 169.7, 175.8. HRMS (CI): m/z [M + H]+ calcd for C29H42NO5 +: 484.3057; found: 484.3064.
  • 24 Preparation of Alcohol 11: To a solution of amide 10 (1.19 g, 2.47 mmol) in anhydrous dichloromethane (15 mL) was added dropwise a solution of TFA (951 μL, 12.3 mmol) in anhydrous dichloromethane (10 mL) at 0 °C. After stirring at 0 °C for 30 min, the solvent was removed under reduced pressure and the residue was redissolved in ethyl acetate. The solution was washed twice with saturated NaHCO3 solution and saturated NaCl solution, the organic phase was dried over MgSO4 and concentrated in vacuo. After purification by column chromatography (silica, pentane/ethyl acetate 75:25), the alcohol 11 (710 mg, 1.95 mmol, 79%) was obtained as a light-yellow oil. Rf (11) = 0.25 (silica, pentane/ethyl acetate 7:3). [α]D 20 –2.3 (c = 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 0.86–0.90 (m, 6 H), 1.15 (d, J = 7.0 Hz, 3 H), 1.23–1.32 (m, 9 H), 1.38–1.44 (m, 1 H), 1.57–1.63 (m, 1 H), 2.45 (quint, J = 7.1 Hz, 1 H), 2.59 (bs, 1 H), 3.56 (dd, J = 7.5, 3.8 Hz, 1 H), 4.01 (dd, J = 18.3, 5.3 Hz, 1 H), 4.15 (dd, J = 18.3, 5.8 Hz, 1 H), 5.15–5.22 (m, 2 H), 6.32–6.34 (m, 1 H), 7.32–7.39 (m, 5 H). 13C NMR (100 MHz, CDCl3): δ = 12.9, 14.1, 14.6, 22.6, 27.1, 29.5, 31.9, 34.0, 35.1, 41.4, 44.1, 67.4, 76.3, 128.4, 128.6, 128.7, 135.0, 170.2, 176.7. HRMS (CI): m/z [M + H]+ calcd for C21H34NO4 +: 364.2482; found: 364.2488.
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  • 28 Preparation of Ester 12: To a solution of compound 11 (416 mg, 1.14 mmol) and Boc-Ala-OH (433 mg, 2.29 mmol) in anhydrous dichloromethane (7.5 mL) were added DCC (378 mg, 1.83 mmol) and 4-pyrrolidinylpyridine (203 mg, 1.37 mmol) at 0 °C. After stirring at room temperature for 2 h, the reaction mixture was filtered and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica, pentane/ethyl acetate 75:25) to give the ester 12 (568 mg, 1.06 mmol, 93%, dr = 81:19 according to 1H NMR) as a colorless oil. Rf (12) = 0.45 (silica, pentane/ethyl acetate 6:4). Major-12: 1H NMR (400 MHz, CDCl3): δ = 0.87 (t, J = 6.2 Hz, 3 H), 0.87 (d, J = 6.5 Hz, 3 H), 1.08–1.13 (m, 1 H), 1.15 (d, J = 7.1 Hz, 3 H), 1.21–1.31 (m, 9 H), 1.37 (d, J = 7.3 Hz, 3 H), 1.41 (s, 9-H), 1.75–1.81 (m, 1 H), 2.69 (quint, J = 7.2 Hz, 1 H), 4.07 (d, J = 4.5 Hz, 2 H), 4.29 (quint, J = 7.4 Hz, 1 H), 5.06 (dd, J = 7.5, 4.4 Hz, 1 H), 5.14–5.22 (m, 3 H), 6.36 (bs, 1 H), 7.31–7.39 (m, 5 H). 13C NMR (100 MHz, CDCl3): δ = 13.6, 14.1, 14.7, 18.3, 22.6, 26.8, 28.3, 29.4, 31.8, 33.5, 34.3, 41.4, 43.6, 49.4, 67.2, 78.6, 79.7, 128.3, 128.5, 128.6, 135.2, 155.2, 170.1, 172.2, 172.7, 173.7. HRMS (CI): m/z [M + H]+ calcd for C29H47N2O7 +: 535.3378; found: 535.3382.
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  • 30 Preparation of Compound 13: The ester 12 (205 mg, 383 μmol) was dissolved in anhydrous dichloromethane (600 µL) and HCl solution (960 μL, 3.83 mmol, 4 M in dioxane) was added dropwise at 0 °C. The solution was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo to obtain the deprotected ester (179 mg, 380 μmol) as a white foam without further purification. Thereafter, the crude product and the tripeptide 4 (185 mg, 460 μmol) were dissolved in anhydrous dichloromethane (4 mL) and two drops of DMF were added for better solubility. After cooling to 0 °C, DIPEA (134 μL, 766 μmol) and HATU (218 mg, 575 μmol) were added and the reaction mixture was stirred at room temperature for 1 h. The solvent was removed under reduced pressure and the residue was redissolved in ethyl acetate. The solution was washed with KHSO4 (1 M), saturated NaHCO3 and saturated NaCl solution, the organic phase was dried over MgSO4 and concentrated in vacuo. After purification by reversed-phase flash chromatography (H2O/MeCN 9:1 → MeCN), the compounds major-13 (195 mg, 238 μmol, dr > 99:1 according to 1H NMR data) and minor-13 (72 mg, 88.0 μmol, dr = 67:34 according to 1H NMR data) were both obtained as white solids. Major-13: Rf (13) = 0.09 (silica, pentane/ethyl acetate 1:1). [α]D 20 –18.6 (c = 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 0.85–0.94 (m, 12 H), 0.95–0.97 (m, 6 H), 1.13 (d, J = 7.0 Hz, 3 H), 1.21–1.30 (m, 10 H), 1.38 (d, J = 7.3 Hz, 3 H), 1.42 (d, J = 7.2 Hz, 3 H), 1.46 (s, 9 H), 1.62–1.68 (m, 1 H), 1.70–1.77 (m, 3 H), 2.08–2.16 (m, 1 H), 2.75 (quint, J = 7.3 Hz, 1 H), 3.79 (t, J = 5.0 Hz, 1 H), 4.02 (dd, J = 18.0, 4.9 Hz, 1 H), 4.20 (dd, J = 17.6, 5.9 Hz, 1 H), 4.30–4.35 (m, 1 H), 4.49 (quint, J = 7.5 Hz, 1 H), 4.60 (quint, J = 7.6 Hz, 1 H), 4.96 (d, J = 4.9 Hz, 1 H), 5.08 (dd, J = 8.8, 3.1 Hz, 1 H), 5.11–5.18 (m, 2 H), 6.43 (d, J = 6.4 Hz, 1 H), 6.86 (bs, 1 H), 7.02 (d, J = 8.0 Hz, 1 H), 7.11 (d, J = 7.2 Hz, 1 H), 7.30–7.37 (m, 5 H). 13C NMR (100 MHz, CDCl3): δ = 13.0, 14.1, 14.2, 17.3, 17.6, 17.9, 19.2, 21.4, 22.6, 23.1, 25.0, 27.1, 28.2, 29.4, 29.9, 31.8, 33.6, 34.1, 40.4, 41.2, 43.1, 48.1, 49.1, 52.7, 61.3, 66.9, 78.6, 81.2, 128.2, 128.4, 128.6, 135.3, 156.6, 170.4, 171.2, 171.7, 171.8, 172.3, 174.4. HRMS (CI): m/z [M–Boc+H]+ calcd for C38H64N5O8 +: 718.4749; found: 718.4747.
  • 31 Chen S, Xu J. Tetrahedron Lett. 1991; 32: 6711
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  • 32 Preparation of Emericellamide A: The depsipeptide 13 (115 mg, 141 μmol) was dissolved in MeOH (1.4 mL) and Pd/C (15.0 mg, 14.0 μmol, 10%) was added. After stirring at room temperature under H2 atmosphere (1 bar) for 2 h, the reaction mixture was filtered and concentrated under reduced pressure to give the crude product (95.6 mg, 131 μmol) as a white solid. Thereafter, the crude product dissolved in anhydrous dichloromethane (600 μL) was cooled to 0 °C and HCl (4 M in dioxane, 350 μL, 1.41 mmol) was added dropwise. After stirring at room temperature for 90 min, the solution was again concentrated under reduced pressure to obtain the globally deprotected depsipeptide (81.0 mg, 121 μmol) as a white solid without further purification. Next, the deprotected crude product was suspended in anhydrous MeCN (141 mL) and FDPP (103 mg, 268 μmol) was added at 0 °C. The suspension was stirred at 0 °C for 20 min and DIPEA (94.0 μL, 536 μmol) was added dropwise over 30 min. Afterwards, the reaction mixture was stirred at room temperature for 15 h and the solvent was removed in vacuo. Purification by reversed-phase flash chromatography (H2O/MeCN 9:1 → MeCN) and preparative HPLC (H2O/ MeCN 6:4 → 1:9) gave emericellamide A (41.1 mg, 67.0 μmol, 48% over three steps) as a white solid. Rf (Emericellamide A) = 0.02 (silica, pentane/ethyl acetate 1:1). [α]D 20 –42.9 (c = 2.0, MeOH) {lit.4 [α]D 30 –42.99 (c = 2.0, MeOH)}. 1H NMR (400 MHz, DMSO-d 6): δ = 0.82 (d, J = 6.0 Hz, 3 H), 0.83 (d, J = 6.8 Hz, 3 H), 0.83 (t, J = 7.0 Hz, 3 H), 0.86 (d, J = 6.6 Hz, 3 H), 0.88 (d, J = 7.0 Hz, 3 H), 0.90 (d, J = 6.8 Hz, 6 H), 0.99–1.13 (m, 2 H), 1.18–1.28 (m, 8 H), 1.22 (d, J = 6.8 Hz, 3 H), 1.24 (d, J = 7.3 Hz, 3 H), 1.53–1.65 (m, 3 H), 1.65–1.70 (m, 1 H), 1.84–1.93 (m, 1 H), 2.87 (dq, J = 9.9, 6.9 Hz, 1 H), 3.62 (dd, J = 17.6, 2.3 Hz, 1 H), 3.98 (dd, J = 8.3, 8.2 Hz, 1 H), 4.00–4.12 (m, 3 H), 4.33 (dd, J = 17.3, 5.5 Hz, 1 H), 4.92 (dd, J = 10.0, 1.8 Hz, 1 H), 7.39 (d, J = 6.8 Hz, 1 H), 7.50 (dd, J = 5.3, 2.3 Hz, 1 H), 7.92 (d, J = 8.5 Hz, 1 H), 8.01 (d, J = 3.8 Hz, 1 H), 8.06 (d, J = 8.3 Hz, 1 H). 13C NMR (100 MHz, DMSO-d 6): δ = 12.9, 13.9, 14.3, 16.3, 18.2, 18.7, 19.0, 20.6, 22.0, 23.2, 24.5, 26.5, 28.8, 30.1, 31.2, 33.2, 33.5, 40.3, 41.0, 42.4, 47.3, 48.2, 51.7, 60.0, 76.6, 168.8, 170.8, 171.1, 171.3, 171.4, 172.9. HRMS (CI): m/z [M + H]+ calcd for C31H56N5O7 +: 610.4174; found: 610.4172.

Corresponding Author

Uli Kazmaier
Saarland University, Organic Chemistry
66123 Saarbrücken
Germany   

Publication History

Received: 22 March 2023

Accepted after revision: 19 April 2023

Accepted Manuscript online:
19 April 2023

Article published online:
30 May 2023

© 2023. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

  • References and Notes

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  • 16 General Procedure (GP): Matteson Homologation In a flame-dried Schlenk tube, a solution of anhydrous dichloromethane (2.5 equiv) in anhydrous THF (2.0 mL/mmol) was cooled to –100 °C and nBuLi (2.5 M in hexane, 1.1 equiv) was added dropwise. After stirring for 30 min at this temperature, boronic ester (1.0 equiv) in anhydrous THF (1.5 mL/mmol) was added slowly and the resulting solution was stirred at –100 °C for a further 30 min. Thereafter, ZnCl2 (1.1–1.3 equiv; flame-dried in vacuo) was dissolved in anhydrous THF (0.8 mL/mmol ZnCl2) and added to the reaction mixture. The solution was stirred for 1 d while warming to room temperature to give the corresponding α-chloroboronic ester. After cooling to 0 °C, nucleophile solution (1.5–2.5 equiv) was added dropwise and the reaction mixture was stirred at room temperature until full conversion. The mixture was then added to a separatory funnel containing saturated NH4Cl-solution and pentane and the phases were separated. The aqueous phase was extracted three times with pentane and the combined organic phases were dried over MgSO4. After removing the solvent in vacuo, the crude product was purified by column chromatography For compounds 8 and 9, the procedure was slightly modified by isolating the α-chloroboronic ester. After the homologation step, the reaction mixture was worked up as described above. For the further conversion, the isolated α-chloroboronic ester and ZnCl2 (1.1 equiv; flame-dried in vacuo) was dissolved in anhydrous THF (4.0 mL/mmol) and cooled to 0 °C. Afterwards, the nucleophile solution (2.5 equiv) was added dropwise and the reaction mixture was stirred at room temperature until full conversion
  • 18 Preparation of Boronic Ester 6: According to the GP,16 methylboronic ester 5 (2.98 g, 11.9 mmol) was stirred with dichloromethane (1.92 mL, 29.8 mmol), nBuLi (5.24 mL, 13.1 mmol), ZnCl2 (1.79 g, 13.1 mmol) and HexMgCl (11.9 mL, 23.8 mmol, 2.0 M in THF) for 3 d. After purification by column chromatography (silica, pentane/Et2O 99:1), the boronic ester 6 (3.20 g, 9.17 mmol, 77%) was obtained as a colorless oil. Rf (6) = 0.60 (silica, pentane/Et2O 97:3). [α]D 20 –37.8 (c = 1.0, CHCl3). 1H NMR (CDCl3, 500 MHz): δ = 0.87 (t, J = 6.9 Hz, 3 H), 0.91–1.00 (m, 2 H), 0.97 (d, J = 7.3 Hz, 3 H), 1.02–1.08 (m, 2 H), 1.10–1.23 (m, 6 H), 1.23–1.34 (m, 12 H), 1.40–1.47 (m, 1 H), 1.57–1.60 (m, 2 H), 1.66–1.68 (m, 2 H), 1.75–1.77 (m, 6 H), 3.81–3.84 (m, 2 H). 13C NMR (CDCl3, 125 MHz): δ = 14.1, 15.8, 22.6, 25.9, 26.0, 26.5, 27.4, 28.2, 28.9, 29.5, 31.9, 33.4, 43.1, 83.1. HRMS (CI): m/z [M + H]+ calcd for C22H42 11BO2 +: 349.3272; found: 349.3281.
  • 19 Preparation of Boronic Ester 7: According to the GP,16 boronic ester 6 (1.71 g, 4.91 mmol) was stirred with dichloromethane (790 μL, 12.3 mmol), nBuLi (2.16 mL, 5.40 mmol) and ZnCl2 (736 mg, 5.40 mmol). The nucleophile solution was prepared by adding (4-methoxyphenyl)methanol (975 μL, 7.85 mmol) to a suspension of NaH (294 mg, 7.36 mmol, 60% in mineral oil) in anhydrous DMSO (10.7 mL) and anhydrous THF (2.7 mL). After addition of the nucleophile solution, the reaction mixture was stirred for 1 d. The crude product was purified by column chromatography (silica, pentane/Et2O 95:5) to give the boronic ester 7 (2.11 g, 4.22 mmol, 86%) as a colorless oil. Rf (7) = 0.63 (silica, pentane/Et2O 9:1). [α]D 20 –16.2 (c = 1.0, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 0.87 (t, J = 7.3 Hz, 3 H), 0.94 (d, J = 6.9 Hz, 3 H), 0.95–1.02 (m, 2 H), 1.04–1.10 (m, 3 H), 1.13–1.34 (m, 16 H), 1.43–1.50 (m, 1 H), 1.58–1.61 (m, 2 H), 1.67–1.69 (m, 2 H), 1.75–1.81 (m, 5 H), 3.11 (d, J = 6.0 Hz, 1 H), 3.80 (s, 3 H), 3.88–3.90 (m, 2 H), 4.36–4.54 (m, 2 H), 6.84–6.86 (m, 2 H), 7.26–7.27 (m, 2 H). 13C NMR (125 MHz, CDCl3): δ = 14.1, 16.9, 22.7, 25.9, 26.0, 26.4, 27.5, 27.6, 28.4, 29.6, 31.9, 33.8, 35.4, 43.0, 55.2, 72.2, 83.6, 113.5, 129.3, 131.5, 158.9. HRMS (CI): m/z [M–H]+ calcd for C31H50 11BO4 +: 497.3802; found: 497.3785.
  • 20 Matteson DS, Peterson ML. J. Org. Chem. 1987; 52: 5116
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  • 21 Preparation of Boronic Ester 8: According to the modified GP,16 boronic ester 7 (1.36 g, 2.73 mmol) was stirred with dichloromethane (439 μL, 6.82 mmol), nBuLi (1.20 mL, 3.00 mmol), ZnCl2 (1.15 g, 8.46 mmol) and MeMgCl (2.27 mL, 6.82 mmol, 3 M in Et2O) for 4 d. After purification by column chromatography (silica, pentane/Et2O 97:3), boronic ester 8 (1.15 g, 2.18 mmol, 80%) was obtained as a colorless oil. Rf (8) = 0.31 (silica, pentane/Et2O 95:5). [α]D 20 –28.4 (c = 1.0, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 0.88 (t, J = 6.9 Hz, 3 H), 0.91 (d, J = 6.6 Hz, 3 H), 0.99 (d, J = 7.6 Hz, 3 H), 0.94–1.03 (m, 4 H), 1.08–1.34 (m, 18 H), 1.55–1.57 (m, 3 H), 1.63–1.67 (m, 2 H), 1.71–1.73 (m, 5 H), 1.79–1.81 (m, 2 H), 3.31 (t, J = 5.7 Hz, 1 H), 3.77–3.79 (m, 2 H), 3.79 (s, 3 H), 4.42–4.57 (m, 2 H), 6.84–6.86 (m, 2 H), 7.25–7.27 (m, 2 H). 13C NMR (125 MHz, CDCl3): δ = 11.8, 14.1, 15.2, 22.7, 25.9, 26.0, 26.4, 27.6, 27.8, 28.5, 29.6, 32.0, 33.8, 35.9, 43.0, 55.3, 72.0, 83.4, 86.2, 113.5, 128.7, 131.8, 158.7. HRMS (CI): m/z [M–H]+ calcd for C33H54 11BO4 +: 525.4120; found: 525.4125.
  • 22 Matteson DS, Beedle EC. Tetrahedron Lett. 1987; 28: 4499
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  • 23 Preparation of Amide 10: According to the modified GP,16 boronic ester 8 (2.12 g, 4.03 mmol) was stirred with dichloromethane (648 μL, 10.1 mmol), nBuLi (1.77 mL, 4.43 mmol), and ZnCl2 (1.70 g, 12.5 mmol) to give the corresponding α-chloroboronic ester (2.30 g, 4.00 mmol). The crude product was dissolved in tBuOH (35 mL) and 2-methyl-2-butene (9.00 mL, 84.9 mmol) was added. A solution of NaClO2 (4.56 g, 40.3 mmol, 80%) and KH2PO4 (5.48 g, 40.3 mmol) in H2O (35 mL) was added and the reaction mixture was stirred at room temperature for 1 d. Thereafter, the reaction solution was acidified with citric acid (10 vol%) and the aqueous phase was extracted three times with Et2O. The combined organic phases were washed with saturated Na2S2O3-solution, dried over MgSO4 and concentrated under reduced pressure to give a mixture of the carboxylic acid 9 and the chiral auxiliary (2.02 g) as a yellow oil without further purification. The mixture was then dissolved in anhydrous dichloromethane (20 mL) and H-Gly-OBn∙HCl (1.06 g, 5.24 mmol) was added. After cooling to 0 °C, DIPEA (1.55 mL, 8.87 mmol), HOBt (679 mg, 4.43 mmol) and EDC∙HCl (850 mg, 4.43 mmol) were added and the reaction solution was stirred at room temperature overnight. The solvent was removed in vacuo and the residue redissolved in ethyl acetate. The solution was washed with KHSO4 solution (1 M), saturated NaHCO3 solution, and saturated NaCl solution, the organic phase was dried over MgSO4 and concentrated under reduced pressure. The residue was dissolved in Et2O (15 mL) and methylboronic acid (265 mg, 4.43 mmol) was added. After stirring for 1 h, the solvent was removed in vacuo and the product was purified by column chromatography (silica, pentane/ethyl acetate 75:25) to give the amide 10 (1.33 g, 2.74 mmol, 68% over two steps) as a colorless oil. Rf (10) = 0.42 (silica, pentane/ethyl acetate 7:3). [α]D 20 –7.5 (c = 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 0.88 (t, J = 6.7 Hz, 3 H), 0.91 (d, J = 6.7 Hz, 3 H), 1.15 (d, J = 7.0 Hz, 3 H), 1.22–1.31 (m, 9 H), 1.41–1.48 (m, 1 H), 1.68–1.73 (m, 1 H), 2.53 (quint, J = 7.1 Hz, 1 H), 3.47 (dd, J = 7.2, 4.0 Hz, 1 H), 3.78 (s, 3 H), 3.88 (dd, J = 18.3, 4.7 Hz, 1 H), 4.15 (dd, J = 18.3, 5.8 Hz, 1 H), 4.45–4.53 (m, 2 H), 5.15 (s, 2 H), 6.55 (t, J = 5.0 Hz, 1 H), 6.82–6.85 (m, 2 H), 7.21–7.24 (m, 2 H), 7.31–7.38 (m, 5 H). 13C NMR (100 MHz, CDCl3): δ = 14.0, 14.1, 15.7, 22.7, 27.3, 29.5, 31.9, 34.1, 35.5, 41.3, 44.5, 55.2, 67.0, 74.9, 85.0, 113.7, 128.3, 128.5, 128.6, 129.2, 130.9, 135.3, 159.1, 169.7, 175.8. HRMS (CI): m/z [M + H]+ calcd for C29H42NO5 +: 484.3057; found: 484.3064.
  • 24 Preparation of Alcohol 11: To a solution of amide 10 (1.19 g, 2.47 mmol) in anhydrous dichloromethane (15 mL) was added dropwise a solution of TFA (951 μL, 12.3 mmol) in anhydrous dichloromethane (10 mL) at 0 °C. After stirring at 0 °C for 30 min, the solvent was removed under reduced pressure and the residue was redissolved in ethyl acetate. The solution was washed twice with saturated NaHCO3 solution and saturated NaCl solution, the organic phase was dried over MgSO4 and concentrated in vacuo. After purification by column chromatography (silica, pentane/ethyl acetate 75:25), the alcohol 11 (710 mg, 1.95 mmol, 79%) was obtained as a light-yellow oil. Rf (11) = 0.25 (silica, pentane/ethyl acetate 7:3). [α]D 20 –2.3 (c = 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 0.86–0.90 (m, 6 H), 1.15 (d, J = 7.0 Hz, 3 H), 1.23–1.32 (m, 9 H), 1.38–1.44 (m, 1 H), 1.57–1.63 (m, 1 H), 2.45 (quint, J = 7.1 Hz, 1 H), 2.59 (bs, 1 H), 3.56 (dd, J = 7.5, 3.8 Hz, 1 H), 4.01 (dd, J = 18.3, 5.3 Hz, 1 H), 4.15 (dd, J = 18.3, 5.8 Hz, 1 H), 5.15–5.22 (m, 2 H), 6.32–6.34 (m, 1 H), 7.32–7.39 (m, 5 H). 13C NMR (100 MHz, CDCl3): δ = 12.9, 14.1, 14.6, 22.6, 27.1, 29.5, 31.9, 34.0, 35.1, 41.4, 44.1, 67.4, 76.3, 128.4, 128.6, 128.7, 135.0, 170.2, 176.7. HRMS (CI): m/z [M + H]+ calcd for C21H34NO4 +: 364.2482; found: 364.2488.
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  • 28 Preparation of Ester 12: To a solution of compound 11 (416 mg, 1.14 mmol) and Boc-Ala-OH (433 mg, 2.29 mmol) in anhydrous dichloromethane (7.5 mL) were added DCC (378 mg, 1.83 mmol) and 4-pyrrolidinylpyridine (203 mg, 1.37 mmol) at 0 °C. After stirring at room temperature for 2 h, the reaction mixture was filtered and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica, pentane/ethyl acetate 75:25) to give the ester 12 (568 mg, 1.06 mmol, 93%, dr = 81:19 according to 1H NMR) as a colorless oil. Rf (12) = 0.45 (silica, pentane/ethyl acetate 6:4). Major-12: 1H NMR (400 MHz, CDCl3): δ = 0.87 (t, J = 6.2 Hz, 3 H), 0.87 (d, J = 6.5 Hz, 3 H), 1.08–1.13 (m, 1 H), 1.15 (d, J = 7.1 Hz, 3 H), 1.21–1.31 (m, 9 H), 1.37 (d, J = 7.3 Hz, 3 H), 1.41 (s, 9-H), 1.75–1.81 (m, 1 H), 2.69 (quint, J = 7.2 Hz, 1 H), 4.07 (d, J = 4.5 Hz, 2 H), 4.29 (quint, J = 7.4 Hz, 1 H), 5.06 (dd, J = 7.5, 4.4 Hz, 1 H), 5.14–5.22 (m, 3 H), 6.36 (bs, 1 H), 7.31–7.39 (m, 5 H). 13C NMR (100 MHz, CDCl3): δ = 13.6, 14.1, 14.7, 18.3, 22.6, 26.8, 28.3, 29.4, 31.8, 33.5, 34.3, 41.4, 43.6, 49.4, 67.2, 78.6, 79.7, 128.3, 128.5, 128.6, 135.2, 155.2, 170.1, 172.2, 172.7, 173.7. HRMS (CI): m/z [M + H]+ calcd for C29H47N2O7 +: 535.3378; found: 535.3382.
  • 29 Samaranayake G, Glasser WG. Carbohydr. Polym. 1993; 22: 1
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  • 30 Preparation of Compound 13: The ester 12 (205 mg, 383 μmol) was dissolved in anhydrous dichloromethane (600 µL) and HCl solution (960 μL, 3.83 mmol, 4 M in dioxane) was added dropwise at 0 °C. The solution was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo to obtain the deprotected ester (179 mg, 380 μmol) as a white foam without further purification. Thereafter, the crude product and the tripeptide 4 (185 mg, 460 μmol) were dissolved in anhydrous dichloromethane (4 mL) and two drops of DMF were added for better solubility. After cooling to 0 °C, DIPEA (134 μL, 766 μmol) and HATU (218 mg, 575 μmol) were added and the reaction mixture was stirred at room temperature for 1 h. The solvent was removed under reduced pressure and the residue was redissolved in ethyl acetate. The solution was washed with KHSO4 (1 M), saturated NaHCO3 and saturated NaCl solution, the organic phase was dried over MgSO4 and concentrated in vacuo. After purification by reversed-phase flash chromatography (H2O/MeCN 9:1 → MeCN), the compounds major-13 (195 mg, 238 μmol, dr > 99:1 according to 1H NMR data) and minor-13 (72 mg, 88.0 μmol, dr = 67:34 according to 1H NMR data) were both obtained as white solids. Major-13: Rf (13) = 0.09 (silica, pentane/ethyl acetate 1:1). [α]D 20 –18.6 (c = 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 0.85–0.94 (m, 12 H), 0.95–0.97 (m, 6 H), 1.13 (d, J = 7.0 Hz, 3 H), 1.21–1.30 (m, 10 H), 1.38 (d, J = 7.3 Hz, 3 H), 1.42 (d, J = 7.2 Hz, 3 H), 1.46 (s, 9 H), 1.62–1.68 (m, 1 H), 1.70–1.77 (m, 3 H), 2.08–2.16 (m, 1 H), 2.75 (quint, J = 7.3 Hz, 1 H), 3.79 (t, J = 5.0 Hz, 1 H), 4.02 (dd, J = 18.0, 4.9 Hz, 1 H), 4.20 (dd, J = 17.6, 5.9 Hz, 1 H), 4.30–4.35 (m, 1 H), 4.49 (quint, J = 7.5 Hz, 1 H), 4.60 (quint, J = 7.6 Hz, 1 H), 4.96 (d, J = 4.9 Hz, 1 H), 5.08 (dd, J = 8.8, 3.1 Hz, 1 H), 5.11–5.18 (m, 2 H), 6.43 (d, J = 6.4 Hz, 1 H), 6.86 (bs, 1 H), 7.02 (d, J = 8.0 Hz, 1 H), 7.11 (d, J = 7.2 Hz, 1 H), 7.30–7.37 (m, 5 H). 13C NMR (100 MHz, CDCl3): δ = 13.0, 14.1, 14.2, 17.3, 17.6, 17.9, 19.2, 21.4, 22.6, 23.1, 25.0, 27.1, 28.2, 29.4, 29.9, 31.8, 33.6, 34.1, 40.4, 41.2, 43.1, 48.1, 49.1, 52.7, 61.3, 66.9, 78.6, 81.2, 128.2, 128.4, 128.6, 135.3, 156.6, 170.4, 171.2, 171.7, 171.8, 172.3, 174.4. HRMS (CI): m/z [M–Boc+H]+ calcd for C38H64N5O8 +: 718.4749; found: 718.4747.
  • 31 Chen S, Xu J. Tetrahedron Lett. 1991; 32: 6711
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  • 32 Preparation of Emericellamide A: The depsipeptide 13 (115 mg, 141 μmol) was dissolved in MeOH (1.4 mL) and Pd/C (15.0 mg, 14.0 μmol, 10%) was added. After stirring at room temperature under H2 atmosphere (1 bar) for 2 h, the reaction mixture was filtered and concentrated under reduced pressure to give the crude product (95.6 mg, 131 μmol) as a white solid. Thereafter, the crude product dissolved in anhydrous dichloromethane (600 μL) was cooled to 0 °C and HCl (4 M in dioxane, 350 μL, 1.41 mmol) was added dropwise. After stirring at room temperature for 90 min, the solution was again concentrated under reduced pressure to obtain the globally deprotected depsipeptide (81.0 mg, 121 μmol) as a white solid without further purification. Next, the deprotected crude product was suspended in anhydrous MeCN (141 mL) and FDPP (103 mg, 268 μmol) was added at 0 °C. The suspension was stirred at 0 °C for 20 min and DIPEA (94.0 μL, 536 μmol) was added dropwise over 30 min. Afterwards, the reaction mixture was stirred at room temperature for 15 h and the solvent was removed in vacuo. Purification by reversed-phase flash chromatography (H2O/MeCN 9:1 → MeCN) and preparative HPLC (H2O/ MeCN 6:4 → 1:9) gave emericellamide A (41.1 mg, 67.0 μmol, 48% over three steps) as a white solid. Rf (Emericellamide A) = 0.02 (silica, pentane/ethyl acetate 1:1). [α]D 20 –42.9 (c = 2.0, MeOH) {lit.4 [α]D 30 –42.99 (c = 2.0, MeOH)}. 1H NMR (400 MHz, DMSO-d 6): δ = 0.82 (d, J = 6.0 Hz, 3 H), 0.83 (d, J = 6.8 Hz, 3 H), 0.83 (t, J = 7.0 Hz, 3 H), 0.86 (d, J = 6.6 Hz, 3 H), 0.88 (d, J = 7.0 Hz, 3 H), 0.90 (d, J = 6.8 Hz, 6 H), 0.99–1.13 (m, 2 H), 1.18–1.28 (m, 8 H), 1.22 (d, J = 6.8 Hz, 3 H), 1.24 (d, J = 7.3 Hz, 3 H), 1.53–1.65 (m, 3 H), 1.65–1.70 (m, 1 H), 1.84–1.93 (m, 1 H), 2.87 (dq, J = 9.9, 6.9 Hz, 1 H), 3.62 (dd, J = 17.6, 2.3 Hz, 1 H), 3.98 (dd, J = 8.3, 8.2 Hz, 1 H), 4.00–4.12 (m, 3 H), 4.33 (dd, J = 17.3, 5.5 Hz, 1 H), 4.92 (dd, J = 10.0, 1.8 Hz, 1 H), 7.39 (d, J = 6.8 Hz, 1 H), 7.50 (dd, J = 5.3, 2.3 Hz, 1 H), 7.92 (d, J = 8.5 Hz, 1 H), 8.01 (d, J = 3.8 Hz, 1 H), 8.06 (d, J = 8.3 Hz, 1 H). 13C NMR (100 MHz, DMSO-d 6): δ = 12.9, 13.9, 14.3, 16.3, 18.2, 18.7, 19.0, 20.6, 22.0, 23.2, 24.5, 26.5, 28.8, 30.1, 31.2, 33.2, 33.5, 40.3, 41.0, 42.4, 47.3, 48.2, 51.7, 60.0, 76.6, 168.8, 170.8, 171.1, 171.3, 171.4, 172.9. HRMS (CI): m/z [M + H]+ calcd for C31H56N5O7 +: 610.4174; found: 610.4172.

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Figure 1 Emericellamide A and B
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Scheme 1 Matteson homologation
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Scheme 2 Synthesis of the peptide fragment 4. Reagents and conditions: (a) piperidine (20 vol% in DMF); 1. 75 °C, 155 W, 15 s; 2. 90 °C, 30 W, 50 s. (b) Fmoc-Leu-OH (4.0 equiv). (c) DIC (4.0 equiv), Oxyma (4.0 equiv), 1. 75 °C, 170 W, 15 s; 2. 90 °C, 30 W, 110 s. (d) Fmoc-Val-OH (4.0 equiv). (e) TFA/TIPS/H2O (95:2.5:2.5), r.t., 90 min. (f) Boc2O (1.3 equiv), NaHCO3 (2.2 equiv), THF/H2O, r.t., 1 d.
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Scheme 3 Synthesis of emericellamide A. Reagents and conditions: (a) CH2Cl2 (2.5 equiv), nBuLi (1.1 equiv), ZnCl2 (1.1–3.1 equiv), THF, –100 °C to r.t., 5 h. (b) nHexMgCl (2.0 equiv), THF, 0 °C to r.t., 3 d. (c) NaOPMB (1.5 equiv), THF/DMSO, 0 °C to r.t., 1 d. (d) MeMgCl (2.5 equiv), ZnCl2 (1.1 equiv), THF, 0 °C to r.t., 4 d. (e) NaClO2 (10 equiv), KH2PO4 (10 equiv), 2-methyl-2-butene (21 equiv), tBuOH/H2O, r.t., 1 d. (f) H-Gly-OBn·HCl (1.3 equiv), HOBt (1.1 equiv), EDC·HCl (1.1 equiv), DIPEA (2.2 equiv), CH2Cl2, 0 °C to r.t., 1 d. (g) MeB(OH)2 (1.1 equiv), Et2O, r.t., 1 h. (h) TFA (5.0 equiv), CH2Cl2, 0 °C, 30 min. (i) Boc-Ala-OH (2.0 equiv), DCC (1.6 equiv), 4-Pyrrolidinylpyridine (1.2 equiv), CH2Cl2, 0 °C to r.t., 2 h. (k) HCl in dioxane (4 M), CH2Cl2, 0 °C to r.t., 2 h. (l) Boc-Val-Leu-Ala-OH (1.2 equiv), HATU (1.5 equiv), DIPEA (2.0 equiv), CH2Cl2, 0 °C to r.t., 2 h. (m) Pd/C (10%), H2, MeOH, r.t., 2 h. (n) HCl in dioxane (4 M), CH2Cl2, 0 °C to r.t., 90 min. (o) FDPP (1.9 equiv), DIPEA (3.8 equiv), MeCN, 0 °C to r.t., 15 h.