Synthesis of Benzothiophene‐Containing 10‐ and 11‐Membered Cyclic Phostones

Abstract

Phosphinate and phosphonate derivatives can serve as useful transition‐state analogues of proteases, as substrate mimics of DNA/RNA‐processing enzymes, and as inhibitors of enzymes catalyzing the biosynthesis of isoprenoids. Synthetic methodologies for the preparation of medium‐sized ring phosphonate‐containing compounds (also known as phostones) are currently limited to a few examples. A synthetic protocol was developed that is amenable to the parallel synthesis of structurally diverse phostones containing a benzo[b]thiophene core, which enables the profiling of such novel compounds in biological screens of potential therapeutic targets.

Synthesis of medium and large phostams, phostones, and phostines

“…It underwent a RCM reaction under the catalysis of Grubbs first generation catalyst in DCM, affording 2-(4-methylphenyl)benzothiophene-fused 2-(benzyloxy)-3,6,7,8,9,10-hexahydro-1,2-oxaphosphecine 2-oxide 26 in 70% yield. After the Pd-catalyzed hydrogenolysis, it was transformed to both cyclic ten-membered phostone 2-(4-methylphenyl)benzothiophene-fused 2-hydroxy-1,2-oxaphosphecane 2-oxide ( 27 ) in 40% yield and acyclic (4-(3-methyl-2-(4-methylphenyl)benzo[ b ]thiophen-4-yl)butyl)phosphonic acid ( 28 ) in 45% yield as a byproduct, which was generated from the Pd-catalyzed arylmethylic cleavage under hydrogenolysis conditions ( Scheme 5 ) [ 22 ].…”

“…The RCM reaction was performed in the presence of Grubbs first generation catalyst in DCM, affording 2-(4-methylphenyl)benzothiophene-fused 2-(benzyloxy)-3,4,5,6,7,10-hexahydro-1,2-oxaphosphecine 2-oxide 31 in 70% yield. After hydrazine reduction and Pd-catalyzed hydrogenolysis, it was converted into 2-(4-methylphenyl)benzothiophene-fused 2-hydroxy-1,2-oxaphosphecane 2-oxide 33 in 70% and 72% yield for the two steps, respectively, without formation of any acyclic byproduct ( Scheme 6 ) [ 22 ].…”

“…It was cyclized via a RCM reaction with Grubbs 1st generation catalyst in DCM, affording 2-(4-methylphenyl)benzothiophene-fused 2-(benzyloxy)-1-oxa-2-phosphacycloundec-8-ene 2-oxide 35 in 70% yield with a ratio of 2:1 for the generated cis - and trans -double bonds. After Pd-catalyzed hydrogenolysis, it was converted into 2-(4-methylphenyl)benzothiophene-fused 2-hydroxy-1-oxa-2-phosphacycloundecane 2-oxide 36 in 83% yield ( Scheme 7 ) [ 22 ].…”

“…In comparison with common ring size phostam, phostone, and phostine derivatives, less attention has been paid to the synthesis of medium and large phostam, phostone, and phostine derivatives. They are also biologically active compounds, such as inhibitors of the human farnesyl pyrophosphate synthase [ 21 – 22 ], antitumor agents [ 23 ], and hapten for the production of the catalytic antibody [ 24 ]. They are also potential chiral ligands in asymmetric catalysis [ 25 ] ( Figure 1 ).…”