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Non-metal-templated approaches to bis(borane) derivatives of macrocyclic dibridgehead diphosphines via alkene metathesis.

ABSTRACT: Two routes to the title compounds are evaluated. First, a ca. 0.01 M CH₂Cl₂ solution of H₃B·P((CH₂)₆CH=CH₂)₃ (1·BH₃) is treated with 5 mol % of Grubbs' first generation catalyst (0 °C to reflux), followed by H₂ (5 bar) and Wilkinson's catalyst (55 °C). Column chromatography affords H₃B·P(n-C₈H₁₇)₃ (1%), H₃B·P((CH₂)₁₃CH₂)(n-C₈H₁₇) (8%; see text for tie bars that indicate additional phosphorus-carbon linkages, which are coded in the abstract with italics), H₃B·P((CH₂)₁₃CH₂)((CH₂)₁₄)P((CH₂)₁₃CH₂)·BH₃ (6·2BH₃, 10%), in,out-H₃B·P((CH₂)₁₄)₃P·BH₃ (in,out-2·2BH₃, 4%) and the stereoisomer (in,in/out,out)-2·2BH₃ (2%). Four of these structures are verified by independent syntheses. Second, 1,14-tetradecanedioic acid is converted (reduction, bromination, Arbuzov reaction, LiAlH₄) to H₂P((CH₂)₁₄)PH₂ (10; 76% overall yield). The reaction with H₃B·SMe₂ gives 10·2BH₃, which is treated with n-BuLi (4.4 equiv) and Br(CH₂)₆CH=CH₂ (4.0 equiv) to afford the tetraalkenyl precursor (H₂C=CH(CH₂)₆)₂(H₃B)P((CH₂)₁₄)P(BH₃)((CH₂)₆CH=CH₂)₂ (11·2BH₃; 18%). Alternative approaches to 11·2BH₃ (e.g., via 11) were unsuccessful. An analogous metathesis/hydrogenation/chromatography sequence with 11·2BH₃ (0.0010 M in CH₂Cl₂) gives 6·2BH₃ (5%), in,out-2·2BH₃ (6%), and (in,in/out,out)-2·2BH₃ (7%). Despite the doubled yield of 2·2BH₃, the longer synthesis of 11·2BH₃ vs 1·BH₃ renders the two routes a toss-up; neither compares favorably with precious metal templated syntheses.

SUBMITTER: Fiedler T

PROVIDER: S-EPMC6142775 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Non-metal-templated approaches to bis(borane) derivatives of macrocyclic dibridgehead diphosphines via alkene metathesis.

Fiedler Tobias T Barbasiewicz Michał M Stollenz Michael M Gladysz John A JA

Beilstein journal of organic chemistry 20180907

Two routes to the title compounds are evaluated. First, a ca. 0.01 M CH2Cl2 solution of H3B·P((CH2)6CH=CH2)3 (1·BH3) is treated with 5 mol % of Grubbs' first generation catalyst (0 °C to reflux), followed by H2 (5 bar) and Wilkinson's catalyst (55 °C). Column chromatography affords H3B·P(n-C8H17)3 (1%), H3B·P((CH2</sub ...[more]

PMID: 30254700

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Project description:Macrocyclic compounds are central to the development of new drugs, but preparing them can be challenging because of the energy barrier that must be surmounted in order to bring together and fuse the two ends of an acyclic precursor such as an alkene (also known as an olefin). To this end, the catalytic process known as ring-closing metathesis (RCM) has allowed access to countless biologically active macrocyclic organic molecules, even for large-scale production. Stereoselectivity is often critical in such cases: the potency of a macrocyclic compound can depend on the stereochemistry of its alkene; alternatively, one isomer of the compound can be subjected to stereoselective modification (such as dihydroxylation). Kinetically controlled Z-selective RCM reactions have been reported, but the only available metathesis approach for accessing macrocyclic E-olefins entails selective removal of the Z-component of a stereoisomeric mixture by ethenolysis, sacrificing substantial quantities of material if E/Z ratios are near unity. Use of ethylene can also cause adventitious olefin isomerization-a particularly serious problem when the E-alkene is energetically less favoured. Here, we show that dienes containing an E-alkenyl-B(pinacolato) group, widely used in catalytic cross-coupling, possess the requisite electronic and steric attributes to allow them to be converted stereoselectively to E-macrocyclic alkenes. The reaction is promoted by a molybdenum monoaryloxide pyrrolide complex and affords products at a yield of up to 73 per cent and an E/Z ratio greater than 98/2. We highlight the utility of the approach by preparing recifeiolide (a 12-membered-ring antibiotic) and pacritinib (an 18-membered-ring enzyme inhibitor), the Z-isomer of which is less potent than the E-isomer. Notably, the 18-membered-ring moiety of pacritinib-a potent anti-cancer agent that is in advanced clinical trials for treating lymphoma and myelofibrosis-was prepared by RCM carried out at a substrate concentration 20 times greater than when a ruthenium carbene was used.

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Non-metal-templated approaches to bis(borane) derivatives of macrocyclic dibridgehead diphosphines via alkene metathesis.

Publications

Non-metal-templated approaches to bis(borane) derivatives of macrocyclic dibridgehead diphosphines via alkene metathesis.

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