Synthesis of novel acetylene-containing amino acids

Summary.  Novel synthetic procedures for the modification of non-proteinogenic acetylene-containing amino acids have been developed. The functionalization either proceeds via zinc/copper-mediated introduction of alkyl substituents, or via tungsten-catalyzed ring-closing alkyne metathesis reactions. Received March 28, 2002 Accepted October 3, 2002 Published online December 18, 2002 Acknowledgements These investigations are supported (in part) by the Netherlands Research Council for Chemical Sciences (CW) with financial aid from the Netherlands Technology Foundation (STW). Authors' address: Floris P. J. T. Rutjes, Prof. Dr., Department of Organic Chemistry, University of Nijmegen, Toernooiveld 1, NL-6525 ED Nijmegen, The Netherlands, E-mail: rutjes@sci.kun.nl  2, selected data: ¹H NMR (300 MHz, CDCl₃) δ 5.32 (d, J = 7.7 Hz, 1H), 4.44–4.40 (m, 1H), 3.76 (s, 3H), 2.75–2.73 (d, J = 5.0 Hz, 2H), 1.44 (s, 9H); ¹³C NMR (75 MHz, CDCl₃) δ 171.0, 155.0, 80.3, 74.6, 52.6, 51.9, 41.7, 28.3, 24.0; mp = 55°C.  Typical procedure for 5: zinc dust (116 mg, 1.408 mmol) was weighed into a 20 mL flask, which was repeatedly evacuated (with heating using a heat gun) and flushed with argon. Dry DMF (0.5 mL, distilled from CaH₂) and 1,2-dibromoethane (9.2 μL, 0.106 mmol) were added and the flask was heated at 80°C for 40 min. The reaction mixture was allowed to cool to room temperature, trimethylsilyl chloride (4 μL, 0.035 mmol) was added and the resulting mixture was stirred vigorously for a further 30 min under argon. Iodocyclohexane (69 μl, 0.528 mmol) was added and stirred at room temperature for 3 h more after which stirring was ceased to settle the zinc. CuCN (41 mg, 0.458 mmol) and LiCl (40 mg, 0.915 mmol) were heated to 150°C for 2 h and cooled to room temperature. Addition of DMF (1 mL) formed a soluble CuCN·2LiCl complex within 5 min. After cooling the Cu-complex to −15°C, the organozinc reagent was added dropwise followed by the bromoacetylene 2 (116 mg, 0.352 mmol). The mixture was allowed to stir overnight at room temperature. Water was added and the suspension was extracted using heptane, washed with brine, dried (MgSO₄) and concentrated. Purification using flash column chromatography (10% EtOAc in heptane) yielded 5 (100 mg, 81%) as a colorless oil. 5: IR ν 3355, 2929, 2852, 2359, 2337, 1749, 1717, 1498, 1447, 1365, 1251, 1181, 1060; ¹H NMR (300 MHz, CDCl₃) δ 5.28 (d, J = 7.7 Hz, 1H), 4.43–4.38 (m, 1H), 3.73 (s, 3H), 2.69–2.63 (m, 2H), 2.13 (m, 1H), 1.73–1.22 (m, 10H), 1.43 (s, 9H); ¹³C NMR (75 MHz, CDCl₃) δ 171.4, 155.0, 88.1, 79.9, 73.8, 52.3, 32.7, 32.7, 28.8, 28.2, 25.8, 24.6, 23.1; HRMS (EI): calculated for C₁₇H₂₇NO₄ 309.1940, found 309.1937.  A solution of the tungsten catalyst (7 mg, 10 mol%) in C₆H₅Cl (2 mL) was treated with a solution of 14 (49.0 mg, 0.120 mmol) in C₆H₅Cl (5.0 mL) under an argon atmosphere and the resulting mixture was heated at 80°C for 3 h. Evaporation followed by flash column chromatography (80% EtOAc in heptane) afforded 15 (21.0 mg, 50%; 64% after correction for starting material) and 14 (16 mg, 33%) as colorless oils. 15: [α]_D =–14.6 (c = 1, CH₂Cl₂); IR ν 3313, 2931, 2865, 2249, 1744, 1667, 1520, 1366, 1170; ¹H NMR (400 MHz, CDCl₃) δ 7.14 (d, J = 8.7 Hz, 1H), 6.08 (d, J = 8.3 Hz, 1H), 4.78 (q, J = 6.8 Hz, 1H), 4.27 (q, J = 7.9 Hz, 1H), 3.73 (s, 3H), 2.17–2.15 (m, 4H), 2.07–1.96 (m, 2H), 1.79–1.52 (m, 4H), 1.45 (s, 9H), 0.89–0.83 (m, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 173.2, 171.8, 155.8, 80.4, 80.2, 79.3, 53.8, 52.5, 51.2, 32.8 (2×), 28.1, 24.6, 24.2, 18.3 (2×); HRMS (EI): calculated for C₁₈H₂₈N₂O₅     

Asymmetric Hydrolysis of (±)-α-Substituted Garboxylic Acid Esters with Microorganisms

Microorganisms that hydrolyze methyl 2-phenylpropionate (1) or reduce 4-phenyl-2-butanone (3) were screened from 250 type cultures. Several Aspergilli and two bacteria hydrolyzed ester 1, and Asp. sojae IAM 2703 preferentially hydrolyzed (R)-isomer of (±)-1, whereas Bacillus subtilis var. niger IFO 3108 and Mycobacterium smegmatis ATCC 10143 preferentially hydrolyzed (S)-isomer. The hydrolysis of the related esters of 1 with these organisms was also examined.     

Reaction of [Pt3(μ-CO)3(PBu3)3] with activated olefins and alkynes: the X-ray-structure of [Pt(CO)(PBu3)(CF3CCCF3)]

The reactions of the triangulo-cluster [Pt₃(μ-CO)₃(P^tBu₃)₃] with activated olefins and alkynes have been examined under various conditions. At low temperature, cluster fragmentation occurs yielding the Pt(0) complexes [Pt(CO)(P^tBu₃)(olefin)] (olefin = maleic anhydride and maleimide), while di(tert-butyl)acetylenedicarboxilate reacts quantitatively giving the dinuclear Pt(0) complex [Pt₂(CO)₂(P^tBu₃)₂(μ-η²:η²-^tBuO₂CCCCO₂^tBu)]. At higher temperature and in the presence of alkyne in large excess, the latter dimer converts quantitatively to the monomers [Pt(CO)(P^tBu₃)(alkyne)] (alkyne = CF₃CCCF₃ and ^tBuO₂CCCCO₂^tBu). The stereochemistry of these complexes has been established by NMR and IR measurements. The structure of [Pt(CO)(P^tBu₃)(CF₃CCCF₃)] was confirmed by X-ray diffraction analysis.     

Structure-based design and synthesis of tricyclic IAP (Inhibitors of Apoptosis Proteins) inhibitors

The design and synthesis of a series of novel tricyclic IAP inhibitors is reported. Rapid assembly of the core tricycle involved two key steps: Rh-catalyzed hydrogenation of an unsaturated bicyclic ring system and a Ru-catalyzed ring closing alkene metathesis reaction. The final Smac mimetics bind to cIAP1 and XIAP BIR3 domains and elicit the desired phenotype in cellular proliferation assays. Dimeric IAP inhibitors were found to possess nanomolar potency in a cellular proliferation assay and favourable in vitro drug-like properties.     

Bi- and Tricyclic Nucleoside Derivatives Restricted in S-Type Conformations and Obtained by RCM-Reactions

Abstract

Ring-closing metathesis (RCM) is applied as a new and powerful technology in the construction of nucleoside analogues that are conformationally restricted in S-type conformations due to additional 3′,4′- and/or 3′,5′-linkages.     

Microwave-assisted RCM for the synthesis of carbocyclic peptides.

Microwave irradiation dramatically improves the efficiency of ring closing metathesis (RCM) reactions of resin-attached peptides and the technology is illustrated by the highly selective synthesis of dicarba analogues of alpha-conotoxin IMI.     

Synthesis of a natural product-inspired eight-membered ring lactam library via ring-closing metathesis

We have prepared a novel speculative eight-membered lactam demonstration library based on the skeletal structure of the potent antitumor marine natural product octalactin A. The basic scaffold was readily constructed in a convergent fashion via ring-closing metathesis chemistry from the corresponding diene amides. A cursory examination of the biological properties of the library validates the relevance and significance of these structures.     

Aqua bridge cleavage and metal ion extrusion by thiocyanate anions in a dicopper complex

Reaction of the imidazolidinyl phenolate-based ligand, H₃L [(2-(2′-hydroxyphenyl)-1,3-bis[4-(2-hydroxyphenyl)-3-azabut-3-enyl]-1,3-imidazolidine)] with Cu(ClO₄)₂·6H₂O produces an aqua-bridged cationic reactant complex [Cu₂(μ-H₂O)(μ-L)][ClO₄]·1.5H₂O (1·1.5H₂O). Solution phase interaction of 1·1.5H₂O with SCN⁻ anions in 1:1 molar ratio leads to [Cu₂(μ-L)(NCS)]·2H₂O (2·2H₂O) that does not possess anymore the reactive aqua bridge but instead a terminal SCN⁻ anion coordinated only to one Cu^II ion. Whereas in 1:2 molar ratio, partial extrusion of the Cu^II ions takes place to generate in situ [Cu(NCS)₃(OH₂)]⁻ anions. These complex anions then quantitatively replace anions in 1·1.5H₂O via ‘anion metathesis’ and concurrently remove the aqua bridge by coordination of linear MeCN to one of the Cu^II ions to give [Cu₂(μ-L)(CH₃CN)][Cu(NCS)₃(OH₂)] (3). The literature unknown [Cu(NCS)₃(OH₂)]⁻ anion forms an intimate H-bonded assembly with the cationic part of 3 to yield a novel [Cu₃] isosceles triangle. The precursor complex is known as antiferromagnetic whereas in 2·2H₂O, the Cu^II (S = 1/2) ions in a dinuclear entity exhibit ferromagnetic interactions (J/k_B = +15.0 K and g = 2.22) to yield an S_T = 1 spin ground state in good agreement with the M versus H data below 8 K.     

Photochemical reactions of transition metal organyl complexes with olefins Part 10. Light-induced formal [5+2] cycloadditions at manganese

Tricarbonyl-η⁵-2,4-dimethyl-2,4-pentadien-1-yl-manganese (1) forms upon UV irradiation in THF at 208 K solvent stabilized dicarbonyl-η⁵-2,4-dimethyl-2,4-pentadien-1-yl-tetrahydrofurane-manganese (2). With butynedioic acid dimethyl ester (3) and diphenylacetylene (5) complex 2 yields tricarbonyl-η⁵-1,2-dimethoxycarbonyl-4,6-dimethyl- cyclohepta-2,4-dien-1-yl-manganese (4) and tricarbonyl-η-4,6-dimethyl-1,2-diphenyl-cyclohepta-2,4-dien-1-yl- manganese (6) in a formal [5+2] cycloaddition. Addition of carbon monoxide and a 1,4-H shift completes the reaction. Propynoic acid methyl ester (7) forms the 2:1 adduct dicarbonyl-η^5:2-1,3-dimethyl-6-methoxycarbonyl-6- (E-2′-methoxycarbonylvinyl)-cyclohepta-2,4-dien-1-yl-manganese (8). The crystal and molecular structure of 8 was determined by X-ray structure analysis. The molecular structures of the complexes 4 and 6 were established by IR and NMR spectroscopy. Formation mechanisms of 4, 6 and 8 are discussed. Crystal data for 8: monoclinic space group P2₁/c, a=802.6(3), b=1136.6(1), c=8872.3(3) pm, β=93.14(2)°, V=1.705 nm³, Z=4.     

Bicyclic tetrapeptides as potent HDAC inhibitors: Effect of aliphatic loop position and hydrophobicity on inhibitory activity

Several histone deacetylase (HDAC) inhibiting bicyclic tetrapeptides have been designed and synthesized through intramolecular ring-closing metathesis (RCM) reaction and peptide cyclization. We designed bicyclic tetrapeptides based on CHAP31, trapoxin B and HC-toxin I. The HDAC inhibitory and p21 promoter assay results showed that the aliphatic loop position as well as the hydrophobicity plays an important role toward the activity of the bicyclic tetrapeptide HDAC inhibitors.