2. Synthesis of (2S, 4S, 5S)-5-(t-Butoxycarbonylamino)-4-(t-Butyldimethylsilyloxy)-2-Isopropyl-7-Methyl Octanoic Acid
M A Lyster, B G Conway Methods Mol Med. 1999;23:453-66. doi: 10.1385/0-89603-517-4:453.
In an effort to produce renm mhibttory peptides, the preparation of (2S,4S,5S)-5-(t-Butoxycarbonylamino)-4-(t-butyldimethylsilyloxy)-2-isopropyl-7-methyl octanotc acid, 15, was carried out (1). This pseudo-dipeptide was used to replace combinattons of leucme coupled with valine in pepttde sequences. The preparation described is the final method developed, after many early less successful attempts. The synthesis mvolves (Fig. 1) the coupling of 1-bromo-5-methyl-2-hexene 3 and N-isovaleryl-L: -prolmol 4 using the opttcal activity of the L: -prolmol to induce optical activrty at the C-2 posmon of 5, a key intermediate (2). After purifying this intermediate through the formatron of its benzoate, the functionalizatlon of the C-4 and C-5 positions is carried out through an epoxtdation to give two stereoisomers. After mesylation and separation of the undesired isomer, 12, it is converted to the desired isomer, 11, through a hydrolysis/lactomzation process, which inverts the C-4 and C-5 centers (3). After formatron of the mesylate, from the recycled material the amine function is introduced through azrde displacement of the mesylate, followed by reduction (4) and protectron with the t-BOC group. Finally, the lactone is opened and the hydroxyl group is protected as the t-butyldtmethylsilyl ether to give the title compound, 15. As can be seen in the procedure, this synthesis was carried out on a large-scale producing 4 8 kg of 15 through a 15-step sequence in an overall yield of 18.5%. Figure 1.
3. Pd(NHC)(cinnamyl)Cl-catalyzed Suzuki cross-coupling reaction of aryl sulfonates with arylboronic acids
Qiwei Wang, Zhen Dai, Xiangjie Di, QingFei Huang, Yuanhua Wang, Jin Zhu Mol Divers. 2020 Nov;24(4):903-911. doi: 10.1007/s11030-019-10001-4. Epub 2019 Oct 16.
A series of N-heterocyclic carbene (NHC)-palladium catalysts have been synthesized and applied to catalyze the Suzuki coupling reaction efficiently between aryl sulfonates and arylboronic acids with the potassium phosphate heptahydrate as a base. The desired yields are obtained even with less reactive aryl tosylates or aryl mesylates as substrates. This method was applied successfully to the synthesis of the (R)-2-(t-butoxycarbonylamino)-3-(biphenyl-4-yl)-propan-1-ol which is the key intermediate of sacubitril, a component of the newly approved antihypertensive drug "Entresto."
