A complex stereochemical relay approach to the antimalarial alkaloid ocimicide A1. Evidence for a structural revision

The core structure of the potent antimalarial alkaloid ocimicide A1 was prepared by a complex stereochemical relay. Computational studies suggest a structural revision of the metabolite is necessary.

SYBR Green-Based Parasite Growth Assay. This proliferation assay was adapted from the malaria SYBR Green I-based fluorescence assay. [7] The intermediates to be tested were added to a 96-well plate with final concentrations of 100 nM, 500 nM, 2 µM/5 µM. A highly synchronized early ring stage parasite culture was added to the plate containing conjugate. Controls were performed using non-infected erythrocytes, infected erythrocytes without conjugate, and infected erythrocytes treated with 2.5 μg/mL and 0.035 μg/mL of blasticidin. Plates were incubated for 72 and 96 h at 37 °C in a gas chamber. After 72 h and 96 h, erythrocytes were lysed with 20 mM Tris (pH 7.5), 5 mM EDTA, 0.008% saponin, 0.08% Triton-X 100, 1× SYBR Green I and incubated for 1 h in the dark at room temperature. Plates were read at 497/520 nm on a Synergy MX, Biotek fluorescent plate reader. The percent inhibition was calculated with no treatment as no inhibition and Blasticidin 2.5 μg/mL treatment as 100% inhibition. NMR Calculations. Following the protocol reported by Hoye and co-workers, [8] structures were generated in GaussView for all diastereomers of protonated ocimicide A2 (2) (at nitrogen 15 and carbons 12, 13, 14 and 17 based on patent numbering [1] ). This produced 32 initial structures, which were imported into BOSS [9] and subjected to a conformational search. Rotamers within 5.02 kcal/mol of the lowest energy structure (8-30 conformers for each diastereomer) were advanced to density functional theory geometry optimization [gas phase, B3LYP/6-31+G(d,p)] in Guassian 09 [10] . Geometry optimized conformers were confirmed as real local-minima by the absence of imaginary frequencies. The chemical shifts of the optimized conformers were calculated at the modified [3] WC04/6-31G(d) level of theory in methanol. Cartesian coordinates (numbering is unique for each conformer, and does not correspond to patent numbering), energy values (in A.U.), and NMR data [ 1 H and 13 C (ppm, δ scale); numbering is consistent with patent [1] ] are presented for each unique conformer (supplementary appendix).

General Experimental Procedures.
All reactions were performed in single-neck, flame-dried, round-bottomed flasks fitted with rubber septa under a positive pressure of argon, unless otherwise noted. Air and moisture-sensitive liquids were transferred via syringe or stainless steel cannula, or were handled in a nitrogen-filled drybox (working oxygen level <1 ppm). Organic solutions were concentrated by rotary evaporation at 30-33 °C. Flash-column chromatography was performed as described by Still et al, [11] employing silica gel (60 Å, 40-63 µm particle size) purchased from Sorbent Technologies (Atlanta, GA). Analytical thin-layered chromatography (TLC) was performed using glass plates precoated with silica gel (1.0 mm, 60 Å pore size) impregnated with a fluorescent indicator (254 nm). TLC plates were visualized by Instrumentation. Proton nuclear magnetic resonance spectra ( 1 H NMR) were recorded at 400 or 500 MHz at 24 °C, unless otherwise noted. Chemical shifts are expressed in parts per million (ppm, δ scale) downfield from tetramethylsilane and are referenced to residual protium in the NMR (CDCl3, δ 7.26; (CD3)2SO, δ 39.5). Data are represented as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet and/or multiple resonances, br = broad, app = apparent), integration, coupling constant in Hertz, and assignment. Proton-decoupled carbon nuclear magnetic resonance spectra ( 13

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infrared spectra (ATR-FTIR) were obtained using a Thermo Electron Corporation Nicolet 6700 FTIR spectrometer referenced to a polystyrene standard. Data are represented as follows: frequency of absorption (cm -1 ), intensity of absorption (s = strong, m = medium, w = weak, br = broad). High-resolution mass spectrometry (HRMS) data were obtained using a Waters UPLC/HRMS instrument equipped with a dual API/ESI high-resolution mass spectrometry detector and photodiode array detector. Unless otherwise noted, samples were eluted over a reverse-phase C18 column (1.7 µm particle size, 2.1 × 50 mm) with a linear gradient of 5% acetonitrile-water containing 0.1% formic acid→95% acetonitrile-water containing 0.1% formic acid over 4 min, followed by 100% acetonitrile containing 0.1% formic acid for 1 min, at a flow rate of 800 µL/min. Nikolayevskiy et al. "A complex stereochemical relay approach to the antimalarial alkaloid ocimicide A1. Evidence for a structural revision." submitted to Chem. Sci.

Synthesis of the enaminone S2:
4-Methoxypyridine (10.0 mL, 98.5 mmol, 1 equiv) was added via syringe to a solution of 2-methyl-1-propenylmagnesium bromide (S1) in tetrahydrofuran (0.50 M, 197 mL, 98.5 mmol, 1.00 equiv) at 24 °C. The reaction mixture was cooled to -23 °C. Benzyl chloroformate (15.5 mL, 108 mmol, 1.10 equiv) was added via syringe to the cold reaction mixture. Upon completion of the addition, the mixture was stirred for 1 h at -23 °C. Aqueous hydrochloric acid solution (10% v/v, 100 mL) was added via syringe to the cold reaction mixture. The reaction mixture was allowed to warm over 30 min to 24 °C, with stirring. The warmed reaction mixture was stirred for 30 min at 24 °C. The product mixture was diluted with ethyl acetate (500 mL). The diluted product mixture was transferred to a separatory funnel that had been charged with saturated aqueous sodium chloride solution (300 mL) and the layers that formed were separated. The aqueous layer was extracted with ethyl acetate (2 × 300 mL). The organic layers were combined and the combined organic layers were dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue obtained was dissolved in dichloromethane (20 mL). Silica gel (25.0 g) was added and the suspension was concentrated to afford a free-flowing powder. The dried powder was transferred to a column of silica gel. Purification by flash-column chromatography (eluting with 30% ethyl acetate-hexanes) afforded the enaminone S2 as a pale, yellow solid (20.9 g, 74%).

Synthesis of the vinylogous amide S3:
Sodium methoxide (1.90 g, 35.1 mmol, 10.0 equiv) was added to a solution of the enaminone S2 (1.00 g, 3.51 mmol, 1 equiv) in methanol (35 mL) in a 100-mL flask that had been fused to a Teflon-coated valve at 24 °C. The reaction vessel was sealed and the sealed vessel was placed in an oil bath that had been preheated to 65 °C. The reaction mixture was stirred and heated for 12 h at 65 °C. The reaction vessel was removed from the oil bath and the product mixture was allowed to cool over 10 min to 24 °C. The cooled product mixture was concentrated to dryness to afford a brown residue. The residue obtained was diluted with ethyl acetate (200 mL). The diluted product mixture was transferred to a separatory funnel that had been charged with water (100 mL) and the layers that formed were separated. The aqueous layer was extracted with ethyl acetate (3 × 150 mL). The organic layers were combined and the combined organic layers were dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue obtained was purified by flash-column chromatography (eluting with 30% ethyl acetate-hexanes initially, grading to 20% methanol-ethyl acetate) to afford the vinylogous amide S3 as a yellow solid (529 mg, >99%).

Synthesis of the carbamate S4:
4-Dimethylaminopyridine (42.8 mg, 350 μmol, 0.10 equiv) was added to a solution of the enaminone S3 (529 mg, 3.50 mmol, 1 equiv) in tetrahydrofuran (7.0 mL) at 24 °C. The reaction mixture was cooled to 0 °C. Triethylamine (2.93 mL, 21.0 mmol, 6.00 equiv) was added dropwise via syringe to the reaction mixture. Upon completion of the addition, the reaction mixture was stirred for 10 min at 0 °C. Di-tert-butyl dicarbonate (965 μL, 4.20 mmol, 1.20 equiv) was added dropwise via syringe to the cold reaction mixture. Upon completion of the addition, the reaction mixture was stirred for 4 h at 0 °C. The product mixture was diluted with ethyl acetate (50 mL). The diluted product mixture was transferred to a separatory funnel that had been charged with water (100 mL) and the layers that formed were separated. The aqueous layer was extracted with ethyl acetate (3 × 50 mL). The organic layers were combined and the combined organic layers were dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated to afford the carbamate S4 was a pale, yellow solid (859 mg, 98%).

Synthesis of the vinyl triflate 9:
A solution of lithium tri-sec-butylborohydride in tetrahydrofuran (1.0 M, 67.0 mL, 67.0 mmol, 1.05 equiv) was added dropwise over 15 min via syringe pump to a solution of the carbamate S4 [16.0 g, 63.8 mmol, 1 equiv, dried by azeotropic distillation with benzene (10 mL)] and Comins' reagent (S5, 27.6 g, 70.2 mmol, 1.10 equiv) in tetrahydrofuran (320 mL) at −78 °C. Upon completion of the addition, the reaction mixture was stirred for 1 h at −78 °C. The cold reaction mixture was warmed over 30 min to 24 °C. The warmed reaction mixture was stirred for 2.5 h at 24 °C. The warmed product mixture was transferred to a separatory funnel that had been charged with aqueous sodium hydroxide solution (10%, 500 mL) and ethyl acetate (500 mL). The layers that formed were separated. The aqueous layer was extracted with ethyl acetate (2 × 400 mL). The organic layers were combined and the combined organic layers were washed sequentially with 1 N aqueous sulfuric acid solution (300 mL), saturated aqueous sodium bicarbonate solution (300 mL), and saturated aqueous sodium chloride solution (300 mL). The organic layer was dried over sodium sulfate and the dried solution was filtered. The filtrate was concentrated and the residue obtained was suspended in dichloromethane (50 mL). The heterogeneous mixture was filtered through a pad of celite. The filtrate was concentrated and the residue obtained was purified by flashcolumn chromatography (eluting with 10% acetone-pentane) to afford a sample of the vinyl triflate 9 contaminated with reagent-derived byproducts. Further purification of this sample by flash-column chromatography (eluting with 5% ethyl acetate-dichloromethane) provided the vinyl triflate 9 as a yellow solid (19.2 g, 78%).

Synthesis of the cyclohexenylquinoline 11:
A 100-mL round-bottomed flask fused to a Teflon-coated valve was charged with the vinyl triflate 9 (1.36 g, 3.90 mmol, 1 equiv) and 2-cyano-6-methoxy-3-(trimethylstannyl)quinoline (10, 1.50 g, 3.90 mmol, 1.00 equiv). Benzene (5.0 mL) was added and the solution was concentrated to dryness. This process was repeated twice. The vessel was sealed and the sealed vessel was transferred to a nitrogen-filled drybox. N,N-dimethylformamide (19.5 mL), tetrakis(triphenylphosphine)palladium (225 mg, 195 μmol, 0.05 equiv), cesium fluoride (1.18 g, 7.79 mmol, 2.00 equiv), and copper iodide (74.2 mg, 390 μmol, 0.10 equiv) were added in sequence. The vessel was sealed and the sealed vessel was removed from the drybox. The reaction mixture was stirred for 1 h at 24 °C. The product mixture was diluted with ethyl acetate (50 mL) and water (50 mL). The diluted product mixture was eluted through a pad of celite (length/diameter = 6/4 cm). The celite pad was washed sequentially with water (50 mL) and ethyl acetate (400 mL). The biphasic filtrate was transferred to a separatory funnel and the layers that formed were separated. The organic layer was washed sequentially with water (3  100 mL) and saturated aqueous sodium chloride solution (100 mL). The organic layer was dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue obtained was purified by flash-column chromatography (eluting with 2% acetone−dichloromethane) to afford the cyclohexenylquinoline 11 as a pale yellow solid (1.63 g, >99%). alkaloid ocimicide A1. Evidence for a structural revision." submitted to Chem. Sci.

Synthesis of the carboxylic acid 12:
2,6-Lutidine (363 μL, 3.13 mmol, 2.00 equiv) and N-methylmorpholine N-oxide (220 mg, 1.88 mmol, 1.20 equiv) were added in sequence to a solution of the cyclohexenylquinoline 11 (656 mg, 1.57 mmol, 1 equiv) in acetone (28 mL) and water (3.1 mL) at 24 °C. A solution of aqueous osmium tetroxide (2% w/w, 491 μL, 31.3 μmol, 0.025 equiv) was added to the reaction mixture at 24 °C. Upon completion of the addition, the resulting reaction mixture was stirred for 12 h at 24 °C. (Diacetoxyiodo)benzene (605 mg, 1.88 mmol, 1.20 equiv) was then added to the reaction mixture. The resulting reaction mixture was stirred for 3 h at 24 °C. An additional portion of (diacetoxyiodo)benzene (302 mg, 0.94 mmol, 0.60 equiv) was added to the reaction mixture and the reaction mixture was stirred for 1 h at 24 °C. The reaction mixture was concentrated to remove acetone (Caution: this operation should be performed in a well-ventilated fume hood). The oily residue in water was diluted with tetrahydrofuran (15.7 mL), tert-butyl alcohol (3.9 mL), and water (12.6 mL). 2-Methyl-2-butene (3.9 mL), monosodium phosphate (1.88 g, 15.7 mmol, 10.0 equiv), and sodium chlorite (991 mg, 11.0 mmol, 7.00 equiv) were added in sequence to the reaction mixture at 24 °C. The reaction mixture was stirred for 1 h at 24 °C. The product mixture was diluted with ether (300 mL). The diluted product mixture was transferred to a separatory funnel that had been charged with 5% aqueous sodium hydroxide solution (200 mL) and the layers that formed were separated. The organic layer was extracted with 5% aqueous sodium hydroxide solution (3 × 150 mL) and water (2 × 100 mL). The aqueous layers were combined and the combined aqueous layers were acidified to pH 4 with concentrated hydrochloric acid solution, to afford an aqueous suspension. The aqueous suspension was transferred to a separatory funnel that had been charged with ethyl acetate (300 mL) and the layers that formed were separated. The aqueous layer was extracted with ethyl acetate (3 × 300 mL). The organic layers were combined and the combined organic layers were dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated to afford the unpurified carboxylic acid 12 as a brown solid. 1 H NMR analysis (400 MHz, CDCl3) indicated >95% conversion to the carboxylic acid 12. The product so obtained was used directly in subsequent steps.
The carboxylic acid 12 was not amenable to purification by flash-column chromatography. Therefore, further characterization was not attempted.
Nikolayevskiy et al. "A complex stereochemical relay approach to the antimalarial alkaloid ocimicide A1. Evidence for a structural revision." submitted to Chem. Sci.
Note: The bromolactone 13 was found to be unstable towards prolonged exposure to silica gel (as indicated by two-dimensional TLC analysis). Therefore, the purification step should be performed as rapidly as possible.

S25
One-pot Synthesis of the epoxide 8: 4-Dimethylaminopyridine (35.5 mg, 291 μmol, 0.19 equiv) and Nbromosuccinimide (311 mg, 1.75 mmol, 1.12 equiv) were added in sequence to a solution of the unpurified acid 12 [1.56 mmol, 1 equiv; assuming quantitative yield in the saponification step, dried by azeotropic distillation with benzene (3 × 10 mL)] in dichloromethane (58 mL) at 24 °C. The reaction mixture was stirred for 1 h at 24 °C. The reaction mixture was concentrated to dryness. The residue so obtained was dissolved in tetrahydrofuran (24 ml) and methanol (48 mL). Potassium carbonate (1.00 g, 7.27 mmol, 4.65 equiv) was added to the reaction mixture at 24 °C. The resulting suspension was vigorously stirred for 1 h at 24 °C. The product mixture was diluted with ethyl acetate (250 mL). The diluted product mixture was transferred to a separatory funnel that had been charged with 100 mM aqueous sodium phosphate buffer solution (pH 7, 200 mL) and the layers that formed were separated. The aqueous layer was extracted with ethyl acetate (3 × 100 mL). The organic layers were combined and the combined organic layers were dried over sodium sulfate. The dried organic solution was filtered and the filtrate was concentrated. The residue obtained was purified by flash-column chromatography (eluting with 10% acetone-dichloromethane) to afford the epoxide 8 as an off-white solid (308 mg, 45% from 11).

Synthesis of the alcohol 7:
In a nitrogen-filled drybox, toluene (11 mL) and lithium bis(trimethylsilyl)amide (20.6 mg, 123 μmol, 1.10 equiv) were added in sequence to a 25-mL round-bottomed flask fused to a Teflon-coated valve that had been charged with the epoxide 8 [49.1 mg, 112 μmol, 1 equiv, dried by azeotropic distillation with benzene (4 × 1.0 mL)]. The vessel was sealed and the sealed vessel was removed from the drybox. The reaction vessel was placed in an oil bath that had been preheated to 103 °C. The reaction mixture was stirred and heated for 2 h at 103 °C. The reaction vessel was removed from the oil bath and the product mixture was allowed to cool over 1 min to 24 °C. The cooled product mixture was transferred to a separatory funnel that had been charged with saturated aqueous ammonium chloride solution (20 mL) and ethyl acetate (30 mL). The layers that formed were separated. The aqueous layer was extracted with ethyl acetate (4 × 30 mL). The organic layers were combined and the combined organic layers were dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated to afford a red viscous oil. 1 H NMR analysis (400 MHz, CDCl3) indicated 75% conversion to the alcohol 7. Purification by flash-column chromatography (eluting with 30% ethyl acetate−dichloromethane, grading to 50% ethyl acetate−dichloromethane, one step) afforded the alcohol 7 as an off-white solid (21.4 mg, 44%) and the recovered epoxide 8 as a pale, yellow solid (9.2 mg, 19%).

Synthesis of the ester 6:
Triethylamine (1.06 mL, 7.59 mmol, 10.0 equiv) and methanesulfonyl chloride (70.1 μL, 910 μmol, 1.20 equiv) were added in sequence to a solution of the alcohol 7 [333 mg, 759 μmol, 1 equiv, dried by azeotropic distillation with benzene (10 mL)] in dichloromethane (10 mL) in a 50-mL round-bottomed flask fused to a Teflon-coated valve at 24 °C. Upon completion of the addition, the reaction mixture was stirred for 1 h at 24 °C. An additional portion of methanesulfonyl chloride (10.0 μL, 130 μmol, 0.17 equiv) was then added at 24 °C. Upon completion of the addition, the reaction mixture was stirred for 30 min at 24 °C. Sodium methoxide (150 mg, 2.78 mmol, 3.67 equiv) and methanol (5.0 mL) were added in sequence to the reaction mixture at 24 °C. The resulting mixture was stirred for 1 min at 24 °C, and then the reaction mixture was concentrated to dryness. Sodium methoxide (328 mg, 6.07 mmol, 8.00 equiv) and methanol (15 mL) were added in sequence to the reaction vessel at 24 °C. The reaction vessel was sealed and the sealed vessel was placed in an oil bath that had been preheated to 65 °C. The reaction mixture was stirred and heated for 12 h at 65 °C. The reaction mixture was concentrated to dryness and the residue obtained was dissolved in tetrahydrofuran (76 mL). Aqueous sulfuric acid solution (2 N, 15 mL) was added to the reaction mixture at 24 °C. The reaction mixture was stirred for 2 h at 24 °C. The product mixture was diluted with dichloromethane (300 mL). The diluted product mixture was poured slowly into a separatory funnel that had been charged with saturated aqueous sodium bicarbonate solution (300 mL) and the layers that formed were separated. The aqueous layer was extracted with dichloromethane (3 × 250 mL). The organic layers were combined and the combined organic layers were dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated to afford the ester 6 as an offwhite solid (321 mg, 96%).

Synthesis of the acid 17:
Aqueous sodium hydroxide solution (1.25 M, 2.3 mL) was added to a solution of the ester 6 (20.4 mg, 46.4 μmol, 1 equiv) in methanol (4.6 mL) in a 10-mL roundbottomed flask fused to a Teflon-coated valve at 24 °C. The reaction vessel was sealed and the sealed vessel was placed in an oil bath that had been preheated to 80 °C. The reaction mixture was stirred and heated for 14 h at 80 °C. The product mixture was allowed to cool over 10 minutes to 24 °C. The cooled product mixture was concentrated to remove methanol. The residue was diluted with water (8.0 mL) and the diluted mixture was acidified to pH 6 with concentrated hydrochloric acid solution. The resulting mixture was loaded onto a column of reverse-phase silica (length/diameter = 15/1 cm). The column was washed with water (20 mL) to remove inorganic salts and the washed column was dried under a stream of nitrogen. The product was then eluted from the dried reverse-phase silica column with methanol (50 mL). The methanol collected and concentrated to afford unpurified acid 17. The product so obtained was used directly in the following step.
Nikolayevskiy et al. "A complex stereochemical relay approach to the antimalarial alkaloid ocimicide A1. Evidence for a structural revision." submitted to Chem. Sci.

Synthesis of the Weinreb amide 18:
Methanesulfonyl chloride (165 μL, 2.13 mmol, 10.0 equiv) was added dropwise to a solution of the unpurified acid 17 [213 μmol, 1 equiv; assuming quantitative yield in the preceding step, dried by azeotropic distillation with benzene (3 × 4.0 mL)] and N,Ndi-iso-propylethylamine (743 μL, 4.26 mmol, 20.0 equiv) in tetrahydrofuran (18 mL) at 0 °C. The reaction mixture was stirred for 30 min at 0 °C. N,O-Dimethylhydroxylamine (385 μL, 5.02 mmol, 23.6 equiv) was added to the reaction mixture at 0 °C. The reaction mixture was stirred for 3 h at 0 °C. The product mixture was diluted with water (5.0 mL). The diluted product mixture was transferred to a separatory funnel that had been charged with saturated aqueous sodium bicarbonate solution (10 mL) and dichloromethane (30 mL). The layers that formed were separated. The aqueous layer was extracted with dichloromethane (4 × 30 mL). The organic layers were combined and the combined organic layers were dried over sodium sulfate. The dried solution was filtered and the filtrate was concentrated. The residue obtained was dissolved in dichloromethane (6.0 mL), and silica gel (800 mg) was added to the diluted product mixture. The resulting suspension was concentrated to afford a free-flowing powder. The dried powder was loaded onto a column of silica gel. Flash-column chromatography (eluting with 10% methanol−ethyl acetate) afforded the Weinreb amide 18 as a white solid (82.9 mg, 83% from 6).

Synthesis of the amine 19:
Trifluoroacetic acid (209 μL) was added to a solution of the ester 6 (6.0 mg, 13.7 μmol, 1 equiv) in dichloromethane (1.4 mL) at 24 °C. Upon completion of the addition, the reaction mixture was stirred for 12 h at 24 °C. The product mixture was concentrated to provide the amine 19 as an off white solid. 1 H NMR analysis (400 MHz, CDCl3) indicated >95% conversion to the secondary amine 19.
The secondary amine 19 was found to be unstable towards neutralization and purification by flash-column chromatography. Therefore, further characterization was not attempted.
Nikolayevskiy et al. "A complex stereochemical relay approach to the antimalarial alkaloid ocimicide A1. Evidence for a structural revision." submitted to Chem. Sci.

Synthesis of the amine 21:
Trifluoroacetic acid (52.4 μL, 68.5 μmol, 30.0 equiv) was added to a solution of the Weinreb amide 18 (10.7 mg, 22.8 μmol, 1 equiv) in dichloromethane (200 μL) at 0 °C. Upon completion of the addition, the reaction mixture was stirred for 12 h at 0 °C. The product mixture was concentrated to provide the secondary amine 21 as an off white solid. 1 H NMR analysis (500 MHz, CD3OD) indicated >95% conversion to the secondary amine 21.
The secondary amine 21 was found to be unstable towards neutralization and purification by flash-column chromatography. Therefore, further characterization was not attempted.  = 0.192). Low-temperature diffraction data (ω-scans) were collected on a Rigaku MicroMax-007HF diffractometer coupled to a Saturn994+ CCD detector with Cu Kα (λ = 1.54178 Å) for the structure of 007-14186. The diffraction images were processed and scaled using Rigaku Oxford Diffraction software (CrysAlisPro; Rigaku OD: The Woodlands, TX, 2015). The structure was solved with SHELXT and was refined against F 2 on all data by full-matrix least squares with SHELXL (Sheldrick, G. M. Acta Cryst. 2008, A64, 112-122). All nonhydrogen atoms were refined anisotropically. Hydrogen atoms were included in the model at geometrically calculated positions and refined using a riding model. The isotropic displacement parameters of all hydrogen atoms were fixed to 1.2 times the U value of the atoms to which they are linked (1.5 times for methyl groups). The only exception is H3, which is freely refining and a part of a hydrogen bond between N3 and O3. The crystal structure reported here contains solvent accessible voids in the unit cell. In spite of numerous attempts, no sensible solvent model could be established, and the solvent is assumed to be disordered within these voids. The crystals had been obtained from a ethyl acetate. The program SQUEEZE was used to compensate for the contribution of disordered solvents contained in voids within the crystal lattice from the diffraction intensities. This procedure was applied to the data file and the submitted model is based on the solvent removed data. Based on the total electron density found in the voids, it is likely that 2 molecules of ethyl acetate molecules are present in the unit cell. See "_platon_squeeze_details" in the .cif for more information. The full numbering scheme of compound 007-14186 can be found in the full details of the X-ray structure determination (CIF), which is included as Supporting Information. CCDC number 1536046 (007-14186) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Center via www.ccdc.cam.ac.uk/data_request/cif.       [3] The modified functional was invoked using WC04 internal option (IOp) statements and the B3LYP functional.

Crystallographic data for the Weinreb amide 18 (Rint
[4] The modified functional was invoked using WC04 internal option (IOp) statements and the B3LYP functional.
[5] The modified functional was invoked using WC04 internal option (IOp) statements and the B3LYP functional.
[6] The modified functional was invoked using WC04 internal option (IOp) statements and the B3LYP functional.