Synthesis of MeBmt and related derivatives via syn-selective ATH-DKR

The unusual α-amino, β-hydroxy acid MeBmt is a key structural feature of cyclosporin A, an important naturally occurring immunosuppressant and antiviral agent. We present a convergent synthesis of MeBmt which relies on new aspects of dynamic kinetic resolution (DKR) to establish simultaneously the chirality at C(2) and C(3). We also show that this route is applicable to the synthesis of other derivatives.

EtOAc, and washed with 1N HCl, 1N NaOH, and brine. Organics were dried over MgSO 4 and concentrated in vacuo, followed by purification by gradient normal phase chromatography to afford the thoioester.

General procedure 'C' for thioester crossed Claisen 2
In general, under N2 at 0°C, magnesium bromide diethyl etherate (1.27 g, 4.91 mmol) was added to a stirred solution of the respective N-acyl benzotriazole (1.402 mmol) in DCM (6 mL), followed by the addition of the respective thioester nucleophile (1.402 mmol) and diisopropylethylamine (0.979 mL, 5.61 mmol). The icebath was removed, and the reaction was allowed to warm to ambient temperature, then left to stir overnight (18h). Upon completion, the reaction was again cooled to 0-5°C, then 10% aqueous HCl (8 mL) was added dropwise. Stirring was continued for 5 min and the mixture was partitioned between EtOAc (30 mL) and H2O (20 mL). The aqueous phase was extracted with EtOAc (2 x 20 mL) and the combined organic extracts were washed with brine, dried over MgSO4, and concentrated in vacuo. The crude b-ketoester products were are purified by gradient column chromatography.

General procedure 'D' for ATH DKR in emulsions 3
Under N 2 , to a solution of an appropriate β-keto derivative (7.60 mmol) in DCM (25 mL) was added sodium formate solution (5N, 50 mL) followed by tetrabutylammonium iodide (5.61 g, 15.19 mmol) and pre-activated Ru-ATH DKR catalyst (0.760 mmol, 10 % loading). After stirring for 40 hours the reaction was added to a separatory funnel and diluted with EtOAc and sat. NaHCO 3 , then the organic phase was separated and the aqueous was extracted with twice more with EtOAc. The combined extracts were dried (MgSO 4 ) and the crude oil was purified by gradient column chromatography, yielding β-hydroxy reduction products.

General procedure 'E' for thioester substitution 2
To a stirred solution of the appropriate β-keto thioester (0.281 mmol) and aniline (

CCDC Deposition number: 1897285
The single crystal X-ray diffraction studies were carried out on a Bruker D8 Platinum 135 CCD diffractometer equipped with Cu K a radiation (l = 1.5478). A 0.217 x 0.053 x 0.051 mm piece of a colorless rod was mounted on a Cryoloop with Paratone oil. Data were collected in a nitrogen gas stream at 125(2) K using f and v scans. Crystal-to-detector distance was 45 mm using variable exposure time (2s-5s) depending on q with a scan width of 2.0°. Data collection was 98.4% complete to 68.00° in q. A total of 33864 reflections were collected covering the indices, -11<=h<=10, -12<=k<=14, -19<=l<=19. 3547 reflections were found to be symmetry independent, with a R int of 0.0549. Indexing and unit cell refinement indicated a primitive, orthorhombic lattice. The space group was found to be P212121. The data were integrated using the Bruker SAINT software program and scaled using the SADABS software program. Solution by direct methods (SHELXT) produced a complete phasing model consistent with the proposed structure.
All nonhydrogen atoms were refined anisotropically by full-matrix least-squares (SHELXL-2014). All carbon bonded hydrogen atoms were placed using a riding model. Their positions were constrained relative to their parent atom using the appropriate HFIX command in SHELXL-2014. All other hydrogen atoms (H-bonding) were located in the difference map. Their relative positions were restrained using DFIX commands and their thermals freely refined. The absolute stereochemistry of the molecule was established by anomalous dispersion using the Parson's method with a Flack parameter of 0.050(34). Crystallographic data are summarized in Table 1.