A practical, convergent route to the key precursor to the tetracycline antibiotics

Abstract

Here we describe a 5-step sequence to prepare the AB enone 1, the key precursor to fully synthetic tetracyclines, that begins with a diastereoselective Michael–Claisen coupling of two simple starting materials, a cyclohexenone (compound 2 or, in a refinement, a substituted variant, vide infra) and the isoxazole ester 3. This advance defines an 8-step linear sequence to 6-deoxytetracycline antibiotics from three components of similar complexity (cyclohexenone 2, isoxazole ester 3, and structurally diverse D-ring precursors) in which sequential diastereoselective Michael–Claisen cyclization reactions form the A- and C-rings, respectively, of the linearly fused ABCD tetracycline skeleton. In addition to providing a readily scalable, practical route to fully synthetic tetracyclines of broad structural diversity, the sequence reported comprises a series of non-obvious stereoselective transformations, including a novel means for C12a hydroxylation.

Total Synthesis and Structural Revision of Viridicatumtoxin B

“…From this point on, the two C15 diastereomers were carried forward as a mixture through several additional steps until separation became convenient. The use of a phenyl ester for the Michael–Dieckmann reaction was critical for success in the union of enone 25 and isoxazole 8 , in agreement with previous observations by White et al [19] and Myers et al [4d] Indeed, the methyl ester counterpart of isoxazole fragment 8 failed to enter this cyclization, leading instead to the initially formed conjugate addition adduct whose subsequently-attempted ring closure under a variety of basic conditions failed.…”

“…[4] Structurally related to the tetracycline antibiotics are the viridicatumtoxins ( 1 – 3 , Figure 1), which constitute an intriguing subclass of naturally occurring potent antibacterial agents. Originally isolated in 1973 from a Penicillium species, [5] viridicatumtoxin A ( 1 ) was structurally elucidated through the aid of an X-ray crystallographic analysis in 1976.…”

“…The reluctance of these substrates to react as projected may be attributed to unwanted rearrangement pathways, including β-elimination/aromatization or ring-expansion/lactone-formation involving the C12a hydroxyl group. [4a,25] …”

“…In support of this notion was the fact that the 1 H NMR spectrum of this mixture acquired at −40 °C displayed two sets of signals. Finally, oxidation of 37 / 37′ with DMP [29] furnished the corresponding C1 ketone (66% yield), which was subjected to hydrogenolysis [4d] (two benzyl ethers and N–O bond; H 2 , Pd black, 98% yield) to afford compound (±)- 38 as shown in Scheme 4. The physical properties of (±)- 38 matched those reported for viridicatumtoxin B [7] except for the presence of the C5 13 C NMR signal at 194.1 ppm for (±)- 38 and the absence of the reported [7] C5 13 C NMR signal at 116.4 ppm.…”

Total Syntheses of HMP-Y1, Hibarimicinone, and HMP-P1

“…The addition of KHMDS was crucial to facilitate the final intramolecular Claisen reaction to construct the F-ring. 30 At this stage, atropisomers (−)- 35a and (+)- 35b were separated and carried forward independently. Elimination of the C6-benzylic phenyl sulfide was accomplished with dimethyl(methylthio)sulfonium tetrafluoroborate (DMTSF) to yield binaphthalenes (−)- 36a and (+)-36b .…”