Synthesis and NMR Characterization of (Z,Z,Z,Z,E,E,ω)-Heptaprenol

Abstract

We describe a practical, multi-gram synthesis of (2Z,6Z,10Z,14Z,18E,22E)-3,7,11,15,19,23,27-heptamethyl-2,6,10,14,18,22,26-octacosaheptaen-1-ol [(Z4,E2,ω)-heptaprenol, 4] using the nerol-derived sulfone 8 as the key intermediate. Sulfone 8 is prepared by the literature route, and is converted in five additional steps (18% yield from 8) to (Z4,E2,ω)-heptaprenol 4. The use of Eu(hfc)3 as an NMR shift reagent not only enabled confirmation of the structure and stereochemistry of 4, but further enabled the structural assignment to a major side-product from a failed synthetic connection. The availability by this synthesis of (Z4,E2,ω)-heptaprenol 4 in gram quantities will enable preparative access to key reagents for the study of the biosynthesis of the bacterial cell envelope.

Reconstitution of Peptidoglycan Cross-Linking Leads to Improved Fluorescent Probes of Cell Wall Synthesis

“… 11 , 12 Cell wall precursor 1 has been synthesized previously. 8d We synthesized the B. subtilis Lipid II substrate 2 in 32 steps by adapting the synthesis of Gram-negative Lipid II 8d , 13 to introduce the carboxamide-containing m -DAP residue. 14…”

Synthesis of Lipid-Linked Oligosaccharides (LLOs) and Their Phosphonate Analogues as Probes To Study Protein Glycosylation Enzymes

“…128 This synthon could then be used in a coupling reaction with any prenyl p-tolyl sulfone made from its prenol precursor in two steps to furnish an elongated polyprenol after reductive removal of the phenylsulfonyl and protecting groups. 129,130 Iterative formation of the polyprenyl p-tolyl sulfone on the newly synthesized polyprenol and condensation with the chloro-intermediate 115 was also performed to access longer polyprenols. Bacterial undecaprenol and all already known dolichol lipids (C70 to C105) of designed geometry and chain length found in eukaryotes have been synthesized following this synthetic strategy.…”

Synthesis and shift-reagent-assisted full NMR assignment of bacterial (Z8,E2,ω)-undecaprenol

“…In support of our studies toward practical access to polyprenol structures, we reported the synthesis of ( Z 4 , E 2 , ω)-heptaprenol ( 3 ). 15 This prenol is an alternative in certain biological assays to the more complex and scarcer bactoprenol. 9 A key discovery made during the course of our synthesis was the advantageous chemical-shift dispersion in its 1 H and 13 C{ 1 H} NMR spectra provided by Eu(hfc) 3 (Europium tris[3-(heptafluoropropyl hydroxymethylene)-(+)-camphorate]).…”

“…10, 11 Synthetic protocols and intermediate characterization are available only for the solid-phase synthesis of Chang et al 11 Our solution-phase synthesis of 1 follows the general strategy established by Sato et al 10 as further refined 15 in our previous synthesis of 3 , wherein a base-mediated reaction of the prenyl sulfone with the prenyl halide is used for prenyl homologation, and culminating in a reductive desulfonylation step. Thus, undecaprenol 1 was synthesized starting from commercial E , E -farnesol 4 using two cycles of sulfone formation and alkylation (using the nerol-derived Z 4 -tetraprenyl bromide 5 15 : the alkylation steps are highlighted in blue in Fig. 1B) and final global deprotection (using Li/EtNH 2 dissolving-metal reduction), in a 61% isolated yield following final chromatographic purification.…”

“…The key building block 5 was constructed in 18 steps from nerol by our earlier method. 15 Undecaprenol 1 was made in 26 convergent steps from nerol. In the course of the global deprotection, we observe as much as 4–15% impurities due to isomerization of the double bonds.…”