Oxyenamides as Versatile Building Blocks for a Highly Stereoselective One‐Pot Synthesis of the 1,3‐Diamino‐2‐ol‐Scaffold Containing Three Continuous Stereocenters

Abstract A highly diastereoselective one‐pot synthesis of the 1,3‐diamino‐2‐alcohol unit bearing three continuous stereocenters is described. This method utilizes 2‐oxyenamides as a novel type of building block for the rapid assembly of the 1,3‐diamine scaffold containing an additional stereogenic oxygen functionality at the C2 position. A stereoselective preparation of the required (Z)‐oxyenamides is reported as well.


Preparation of the aldehydes
Typical procedure 2 (TP2) To a solution of N-protected aminoalcohol S1 (1.0 equiv) in ethylacetate (5 mL/mmol) was added 2iodoxybenzoic acid (2.0 equiv) in one portion. The resulting suspension was refluxed for 3 h. After TLC analysis showed complete consumption of the starting material the reaction mixture was filtered through a short plug of Celite and the residue washed with ethylacetate. The solvents were removed under reduced pressure and the crude product was dried for 2-3 h under oil pump vacuum (10 -2 mbar) to afford the desired aldehyde. All aldehydes of type 2 are not stable and rapidly decompose upon prolonged storage. Therefore, all aldehydes were used directly without further purification. [7]

Preparation of the (Z)-Oxyenamides/(Z)-Oxyencarbamates
Typical procedure 3 (TP3) To a stirred solution of triethylamine (1.7 equiv) and the corresponding acyl chloride (1.3 equiv) in dichlormethane (2 mL/mmol) was added dropwise a solution of the aldehyde 2a-c (1.0 equiv) in dichlormethane (2 mL/mmol) over 5 min. The reaction mixture was stirred for 1 h at room temperature. After TLC analysis showed complete consumption of the aldehyde, saturated NaHCO3 solution was added (20 mL). The organic layers were separated and the aqueous phase was extracted with dichlormethane (2x 30 mL). The combined organic layers were dried over Na2SO4, filtered and the solvents were evaporated under reduced pressure. Purification by flash chromatography afforded the desired (Z)-oxyenamide/(Z)-oxyencarbamate 1a-e as analytically pure product. All oxyenamides of type 1 tend to decompose upon contact to any type of acid. Therefore, column chromotography was performed with 0.2 vol% NEt3 as additive. CDCl3 for NMR spectroscopy was passed through short plug of basic alumina before use.

Preparation of N,O-Acetals
Typical procedure 4 (TP4) A flame dried and nitrogen flushed Schlenk tube, equipped with a septum and a magnetic stirrer, was charged with (Z)-oxyenamide/-encarbamate 1a-e (1.0 equiv), N-acylimine precursor 3a (1.1 equiv) and dichloromethane (10 mL/mmol). The solution was cooled to -55 °C and SiCl4 (2.0 equiv) was added dropwise. The resulting mixture was warmed to -10 °C within 2.5 h to 4 h. After TLC analysis of an aliquot showed complete consumption of the (Z)-oxyenamide/-encarbamate, methanol (3 mL/mmol) was added at -10 °C. The resulting solution was warmed to room temperature and stirred for 10 min. S11 Saturated aqueous NH4Cl (20 mL) was added and the organic layer was separated. The aqueous phase was extracted with dichloromethane (2x 25 mL). The combined organic layers were dried over Na2SO4
Triethylsilane (6.0 equiv) was added at -50 °C. The solution was allowed to slowly warm to room temperature and stirred for additionally 24 h at room temperature. After TLC analysis of an aliquot showed complete consumption of the starting material, the reaction was quenched with saturated aqueous NH4Cl (3 mL) and diluted with dichloromethane. The organic layer was separated and the aqueous phase was extracted with dichloromethane (2x 5 mL). The combined organic layers were dried over Na2SO4 and the solvents were evaporated under reduced pressure. Purification by flash chromatography afforded the desired 1,2-syn-1,3-diamin-2-ol 5a-e as analytically pure product.
The data were scaled using the frame scaling procedure in the X-AREA program system (Stoe & Cie, 2002) [2] . The structures were solved by direct methods using the program SHELXS-2014/6 and refined against F 2 with full-matrix least-squares techniques using the program SHELXL-2014/6. [3] The crystal of 3c was an extremely thin weakly diffracting needle. All H atoms were geometrically positioned and refined using a riding model.
In 6b and in 6c, the H atoms bonded to N were freely refined.
Data for 6a, 7a, 7c, 7g, 7h and 7i (CCDC 2097900, 2097895, 2097896, 2097898, 2097987, 2097899) were collected at 150.0(1) K on a Gemini S Ultra by Rigaku Oxford Diffraction, equipped with a molybdenum (λ = 0.71073 Å) and a copper (λ = 1.54184 Å) radiation source and a low-temperature control device. Due to the positioning of the two sources in the device, data collection is somewhat limited to smaller angles, which may result in alerts in some checkcif files. Absorption correction was done with CrysAlis Pro 1.171.38.41 and 1.171.40.67a, respectively. All structures were solved using the software programs SHELXS-2018/3, and the positions of all non-hydrogen atoms were refined with SHELXL-2018/3. [3] In 6a, 7a, 7c, 7g, 7h and 7i the hydrogen atoms were calculated and refined using a riding model and isotropic thermal parameters.
In structure 7a chloroform and water were embedded. In structure 7h dichlormethane was embedded.
Due to multiple misplacements and an unsatisfying solution a SQUEEZE [10] calculation was performed before refinement with SHELXL-2018/3.