WO2014059436A1 - Ajustement électronique de sélectivité de site - Google Patents

Ajustement électronique de sélectivité de site Download PDF

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Publication number
WO2014059436A1
WO2014059436A1 PCT/US2013/064947 US2013064947W WO2014059436A1 WO 2014059436 A1 WO2014059436 A1 WO 2014059436A1 US 2013064947 W US2013064947 W US 2013064947W WO 2014059436 A1 WO2014059436 A1 WO 2014059436A1
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Prior art keywords
site
ara
functionalization
electron
reagent
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PCT/US2013/064947
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English (en)
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Martin D. Burke
Brandon C. WILCOCK
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The Board Of Trustees Of The University Of Illinois
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Publication of WO2014059436A1 publication Critical patent/WO2014059436A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins

Definitions

  • Structurally complex small molecules have an extraordinary capacity to perform a wide range of useful functions. Accessing structural derivatives of these compounds, however, represents a major bottleneck in efforts to understand and/or optimally harness this capacity.
  • Site-selective functionalization represents a frontier synthesis strategy with outstanding potential for addressing this limitation.
  • Site-selective acylation has emerged as a particularly promising approach for accessing derivatives of polyhydroxylated natural products, with the capacity for exceptional step-efficiency relative to total synthesis.
  • Current strategies for achieving selectivity in this context include modifying the steric and/or stereochemical features of the acylating reagents, or utilizing lipase enzymes. However, suboptimal site selectivities too often limit the preparative utility of this approach.
  • New strategies for maximizing site selectivity or enabling the development of reagents that can override substrate bias to achieve site-divergent functionalizations stand to address these important limitations and thereby have a major impact on small molecule science.
  • An aspect of the invention is a method of site-selective functionalization of a substrate molecule having a plurality of potential sites for functionalization.
  • the method comprises the steps of:
  • a functionalizing reagent for reaction with at least one potential site for functionalization of a substrate molecule having a plurality of potential sites for functionalization
  • S represents the substrate molecule having a plurality of potential sites for
  • R(D) represents the functionalizing reagent comprising a functional group
  • D represents the functional group
  • S(D) represents a product molecule having the functional group linked to a desired site of the substrate molecule.
  • the functionalizing reagent is an electron-rich functionalizing reagent.
  • the functionalization is acylation.
  • the functionalizing reagent is achiral.
  • the functionalizing reagent is a /?ara-substituted benzoyl chloride.
  • An aspect of the invention is a method of C2' -selective acylation of amphotericin B
  • the method comprises the step of contacting amphotericin B with an electron-rich /?ara-substituted benzoyl chloride.
  • An aspect of the invention is a method of C2' -selective acylation of amphotericin B.
  • the method comprises the step of contacting a compound of formula I
  • P 1 and P 2 represent hydrogen or together form a para -methoxy phenyl- substituted methine
  • P 3 and P 4 represent hydrogen or together form a /?ara-methoxy phenyl-substituted methine
  • P 5 represents hydrogen or methyl
  • P 6 represents hydrogen or methyl
  • P 7 represents hydrogen or -C(0)Bn
  • P 1 , P , P J , F, P 3 , P°, and P' is not hydrogen.
  • An aspect of the invention is a method of C2' -selective acylation of amphotericin B.
  • the method comprises the step of contacting a compound of formula II
  • the electron-rich /?ara-substituted benzoyl chloride is achiral.
  • the electron-rich /?ara-substituted benzoyl chloride is selected from the group consisting of /?-N,N-dimethylaminobenzoyl chloride and /?-tertbutylbenzoyl chloride.
  • An aspect of the invention is compound 6
  • PMP represents /?ara-methoxyphenyl
  • R represents diethylisopropylsilyl.
  • An as ect of the invention is compound 10
  • An aspect of the invention is compound 7
  • PMP represents /?ara-methoxyphenyl
  • R represents diethylisopropylsilyl.
  • An aspect of the invention is a method of making compound 7.
  • the method comprises the reaction scheme
  • Figure la is a graph depicting the Hammond postulate applied to site selectivity. More electron-rich acylpyridinium ions are predicted to react via a more product-like transition state in which the site-discriminating interactions between the acylating reagent and the polyol substrate are magnified. These enhanced interactions increase the difference in activation energies ( ⁇ ') for the acylation of one hydroxyl group (solid line) versus another (dashed line).
  • Figure lb depicts Amphotericin B (AmB) and a putative interaction between the hydroxyl group at C2' and ergosterol.
  • Figure lc is a schematic representation depicting a strategy for site-selective
  • Figure 2a is a Hammett study of site-selective acylation. As the electron-withdrawing capacity of the substituent increased, the selectivity decreased and the rate increased. Values for the % C2'-OH selectivity represent the average of three trials.
  • Figure 2b is a Hammett plot of the log of the ratio of the product monoacylated at C2' to all other products as a function of a para . Values for the ratio of site isomers represent the average of three trials.
  • Figure 2c is a Hammett plot of the log of the initial rate as a function of a para . Values for the initial rate represent the average of three trials.
  • Figure 2d is a plot of the ratio of site isomers as a function of the initial rate. Values for the ratio of site isomers and initial rate represent the average of three trials.
  • Figure 3 is a schematic depicting selective functionalizations at the C2' position of AmB.
  • Electronic tuning of the acyl donor enables selective acylation at the C2' hydroxyl of intermediate 1.
  • the acyl group acts as a temporary protecting group that is removed after orthogonal protection of the remaining hydroxyl groups leaving only the C2' hydroxyl exposed.
  • the C2' hydroxyl can then undergo a variety of functionalizations such as
  • the Hammond postulate predicts that as a reaction becomes less exothermic, the corresponding transition state will become more product-like. As a consequence, any potentially site-discriminating interactions between reagents and substrates should be amplified, thus leading to enhanced site selectivities. Although the Hammond postulate has classically been invoked to explain a variety of different trends in reactivity, a general approach for engaging this phenomenon to maximize site-selective functionalizations of complex small molecules has not, to the best of our knowledge, been previously reported.
  • amphotericin B (Fig. lb) represents an outstanding platform for testing this hypothesis, and recent advances have made the hydroxyl group at C2' a particularly important target for site-selective acylation (Fig. lb).
  • AmB primarily kills yeast via simply binding ergosterol, a lipid that is vital for many aspects of yeast physiology. Gray, KC et al, Proc. Natl. Acad. Sci. U.S.A. 109, 2234-2239 (2012). Competitive binding of cholesterol in human cells likely plays an important role in the substantial toxicity of this clinically vital antifungal agent. Palacios, DS et al, Proc. Natl. Acad. Sci. USA 108, 6733-6738 (2011). Sterol binding is also critical for formation of the AmB-based ion channel, (Palacios, DS et al, Proc. Natl. Acad. Sci.
  • the mycosamine appendage is required for binding both ergosterol and cholesterol
  • DIPEA diisopropylethylamine
  • C2' selectivity is the percent of the total product mixture that is monoacylated at C2'. Results represent the average of three trials.
  • Compound 6 having a uniquely exposed hydroxyl group at C2' has proven to be a highly versatile intermediate.
  • efficient deoxygenation at C2' to form 7 was achieved via nucleophilic displacement of the axial C2' -hydroxyl group to generate the equatorial iodide 46 followed by a novel AgO Ac-mediated reductive deiodination with NaBH 4 .
  • epimerization at C2' 34 to yield 8 was readily achieved using standard Mitsunobu conditions. This approach also provides unique access to AmB-small molecule conjugates linked via the C2' hydroxyl group.
  • Electronic tuning might also prove to be generally useful in the development of reagent- based site-divergent functionalization reactions. For example, if two different acylation catalysts produce modest levels of site-divergency with the same acid chloride, electronic tuning of the acid chloride should lead to parallel optimization of both site-selectivities, thereby yielding highly optimized site-divergency. Moreover, we found that site-divergency can also be achieved via concomitant electronic tuning of both an acylpyridinium ion and its carboxylate counterion, which is accessible by simply modifying the corresponding readily available anhydride donors.
  • Amphotericin B was a gift from the Bristol-Myers Squibb Company. All other commercially available reagents were obtained from Sigma-Aldrich, TCI America, Fischer Scientific, Combi-Blocks Inc., and Oakwood Products. Chemicals were used without further purification unless otherwise specified. Camphorsulfonic acid was purified before use by recrystallization with ethyl acetate. Triethyl amine, diisopropylethyl amine, pyridine, and 2,6- lutidine were freshly distilled over calcium hydride under nitrogen atmosphere. All solvents were obtained from a solvent purification system utilizing packed columns as described by Pangborn and coworkers (Organometallics 1996, 15, 1518-1520).
  • Phenyl acetic acid (662 mg, 4.86 mmol, 3 eq) was dissolved in THF (30 mL), Trimethyl acetyl chloride (400 ⁇ ,, 3.25 mmol, 2 eq) was added followed by triethyl amine (900 ⁇ , 6.46 mmol, 4 eq). The reaction was allowed to stir for 8 hrs at room temperature. The reaction was placed in an ice bath, and DMSO (30 mL) was added over 2 min as it cooled. Once the reaction reached 0 °C, AmB (1.5 g, 1.62 mmol, 1 eq) was added. The yellow-tan suspension slowly became soluble over 90 min stirring at 0 °C.
  • Camphorsulfonic acid (94 mg, 405 ⁇ , 0.25 eq) was added, and the yellow-tan suspension slowly became soluble over 45 min of stirring at 0 °C.
  • the reaction was quenched by triethyl amine (57 ⁇ , 405 ⁇ , 0.25 eq) at 0 °C.
  • the reaction solution was concentrated by approximately 2/5 by rotary evaporation and poured into diethyl ether:hexane 1 : 1 (1.2 L) while stirring rapidly. After stirring 15 min, the yellow precipitate was collected in a Buchner funnel equipped with Whatman 50 filter paper by vacuum filtration. The precipitate was washed 3 times with diethyl ether (200 mL). The powder was dried under vacuum for 8 hrs.
  • the reaction was diluted with diethyl ether and quenched with saturated sodium bicarbonate at 0 °C.
  • the reaction was extracted with diethyl ether and washed with 1 M copper sulfate until no white precipitate was observed.
  • the organic layers were washed twice with water and then once with saturated sodium chloride.
  • the organic layers were then dried over sodium sulfate and filtered.
  • the solvent was removed under reduced pressure and column chromatography (Si0 2 ; EtOAc:Hexane 1 :9— " 1 :4) purification yielded SI2 as a yellow-orange solid (2.24 g, 1.13 mmol, 72%).
  • SI2 (550 mg, 278 ⁇ , 1 eq) was dissolved in THF:MeOH 1 :2 (13.5 mL), and KCN (27.0 mg, 417 ⁇ , 1.5 eq) was added. The reaction was heated to 40 °C for 2 days. The reaction was diluted with diethyl ether and washed with water three times followed by a wash of saturated sodium chloride. The organic layers were dried over sodium sulfate and filtered. The solvent was removed under reduced pressure and column chromatography (Si0 2 ;
  • SI3 (320 mg, 166 ⁇ , 1 eq) was placed in a vial and azeotropically dried with toluene and placed under vacuum overnight.
  • the vial was backfilled with argon and DMPU (6.6 mL) was added.
  • Sodium borohydride 50 mg, 1.33 mmol, 8 eq
  • silver(I) acetate 42 mg, 249 ⁇ , 1.5 eq
  • the reaction was heated in the range of 50-55°C for 3 hrs. After 3 hrs, an aliquot was removed in the glovebox every 30 min to monitor the reaction by TLC. The reaction was allowed to run to approximately 85% conversion until the rate of decomposition exceeded conversion of the starting material.
  • the reaction was cooled to room temperature and then diluted with dry diethyl ether that had been cooled to 0°C.
  • the reaction was quenched with saturated sodium bicarbonate cooled to 0°C.
  • Room temperature diethyl ether was used to extract the aqueous layer.
  • the organic layer was then washed with water twice. A final wash of saturated sodium chloride was performed, and the organic layers were dried over sodium sulfate and filtered.
  • the solvent was removed under reduced pressure and column chromatography (Si0 2 ; EtOAc:Hexane 3: 17) purification yielded 7 as a yellow-orange solid (89.8 mg, 49.8 ⁇ , 30%).
  • the reaction was found to be dependent upon the identity of the protecting group on the C3 ' amine. Extensive elimination or inactivity was observed for other protecting groups.
  • Ergosterol 400 mg, 1.01 mmol, 1 eq
  • succinic anhydride (1.01 g, 10.1 mmol, 10.0 eq) were azeotroped with toluene (3x 1.0 mL) in a 40 mL vial.
  • Dry pyridine (20 mL 0.05 M) was then added followed by dimethylaminopyridine (DMAP) (154.2 mg, 1.26 mmol, 1.25 eq).
  • DMAP dimethylaminopyridine
  • the reaction was sealed with a teflon lined cap and heated to 140°C for 16 hrs.
  • the resulting black solution was extracted with HCl (10% v/v) and EtOAc.
  • the organic phase was dried with sodium sulfate, filtered, and concentrated. Chromatography (Si0 2 ; EtOAc:Hexane 1 :5 with 1%) AcOH) purification yielded A as a white solid (282 mg, 0.57 mol, 56%
  • flow rate lmL/min
  • gradient 5% MeCN in water for 2 min then 5 ⁇ 54% MeCN in water over 3 min then 54 ⁇ 95% MeCN in water over 13 min, hold 95% MeCN in water for 7 min followed by gradient to 5% water, 75% MeCN, 20% THF over 3 min then increasing to 5% water, 95% THF in one min and holding 95% THF in water for 3 min.
  • the conversion and ratio of products were determined by integration of the HPLC traces.
  • the structure of the mono-acylated products was determined by multi-dimensional NMR and HRMS (Example 3). Conversion was calculated as the sum of the product peak areas over the total area. % C2' selectivity was calculated as the area for the C2' mono-acylated product over the total product area.
  • the ratio of site isomers used in the Hammett analysis is the C2' mono-acylated product over the sum of the other product areas.
  • Example 2 The mono-acylated products of the acylation reactions were purified by preparative HPLC. Each product was then resubmitted to acylating conditions:

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Abstract

Selon la présente invention, la fonctionnalisation à sélectivité de site de l'amphotéricine B a été obtenue en modifiant simplement la nature électronique des réactifs. Une analyse de Hammett est compatible avec l'association de ce phénomène au postulat de Hammond : l'ajustement électronique à un état de transition plus proche du produit amplifie les interactions à discrimination de site entre un réactif et son substrat. L'ajustement électronique d'un donneur d'acylpyridinium et de son contre-ion carboxylate favorise plus avant la fonctionnalisation de site divergent. Une série de modifications de l'un des nombreux groupes hydroxyle liés au produit naturel formant un canal ionique amphotéricine B a été obtenue.
PCT/US2013/064947 2012-10-12 2013-10-15 Ajustement électronique de sélectivité de site WO2014059436A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016014779A1 (fr) * 2014-07-23 2016-01-28 The Board Of Trustees Of The University Of Illinois Dérivés macrolides de polyènes antifongiques à toxicité réduite pour les mammifères
JP2017518982A (ja) * 2014-05-16 2017-07-13 ザ ボード オブ トラスティーズ オブ ザ ユニヴァーシティ オブ イリノイＴｈｅ Ｂｏａｒｄ Ｏｆ Ｔｒｕｓｔｅｅｓ Ｏｆ Ｔｈｅ Ｕｎｉｖｅｒｓｉｔｙ Ｏｆ Ｉｌｌｉｎｏｉｓ 低減された毒性を有するアンホテリシンｂ誘導体
US10683318B2 (en) 2014-10-17 2020-06-16 The Board Of Trustees Of The University Of Illinois Scalable synthesis of reduced toxicity derivative of amphotericin B

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BRANDON C. WILCOCK ET AL: "C2'-OH of Amphotericin B Plays an Important Role in Binding the Primary Sterol of Human Cells but Not Yeast Cells", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 135, no. 23, 12 June 2013 (2013-06-12), pages 8488 - 8491, XP055090253, ISSN: 0002-7863, DOI: 10.1021/ja403255s *
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GAFFNEY P R J ET AL: "Synthesis of 1-O-stearoyl-2-O-arachidonoyl-sn-glycer-3-yl-d-myo-inositol 3,4,5-trisphosphate and its stereoisomers", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, PERGAMON, GB, vol. 7, no. 24, 16 December 1997 (1997-12-16), pages 3171 - 3176, XP004136606, ISSN: 0960-894X, DOI: 10.1016/S0960-894X(97)10166-4 *
GRAY, KC ET AL., PROC. NATL. ACAD. SCI. U.S.A., vol. 109, 2012, pages 2234 - 2239
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MITCHELL P. CROATT ET AL: "Probing the Role of the Mycosamine C2'-OH on the Activity of Amphotericin B", ORGANIC LETTERS, vol. 13, no. 6, 18 March 2011 (2011-03-18), pages 1390 - 1393, XP055090264, ISSN: 1523-7060, DOI: 10.1021/ol2000765 *
NAONOBU TANAKA ET AL: "Stelliferins JN, isomalabaricane-type triterpenoids from Okinawan marine spongecf", TETRAHEDRON, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 67, no. 35, 26 April 2011 (2011-04-26), pages 6689 - 6696, XP028248824, ISSN: 0040-4020, [retrieved on 20110501], DOI: 10.1016/J.TET.2011.04.095 *
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PALACIOS, DS, PROC. NATL. ACAD. SCI. USA, vol. 108, 2011, pages 6733 - 6738
WILCOCK BRANDON C ET AL: "Electronic tuning of site-selectivity", NATURE CHEMISTRY, NATURE PUBLISHING GROUP, GB, vol. 4, no. 12, 1 December 2012 (2012-12-01), pages 996 - 1003, XP009174622, ISSN: 1755-4330 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2017518982A (ja) * 2014-05-16 2017-07-13 ザ ボード オブ トラスティーズ オブ ザ ユニヴァーシティ オブ イリノイＴｈｅ Ｂｏａｒｄ Ｏｆ Ｔｒｕｓｔｅｅｓ Ｏｆ Ｔｈｅ Ｕｎｉｖｅｒｓｉｔｙ Ｏｆ Ｉｌｌｉｎｏｉｓ 低減された毒性を有するアンホテリシンｂ誘導体
EP3142672A4 (fr) * 2014-05-16 2017-11-15 The Board of Trustees of the University of Illionis Dérivé d'amphotéricine b à toxicité réduite
WO2016014779A1 (fr) * 2014-07-23 2016-01-28 The Board Of Trustees Of The University Of Illinois Dérivés macrolides de polyènes antifongiques à toxicité réduite pour les mammifères
US10683318B2 (en) 2014-10-17 2020-06-16 The Board Of Trustees Of The University Of Illinois Scalable synthesis of reduced toxicity derivative of amphotericin B

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