Callipeltosides A, B and C: Total Syntheses and Structural Confirmation

Abstract

Since their isolation almost 20 years ago, the callipeltosides have been of long standing interest to the synthetic community owing to their unique structural features and inherent biological activity. Herein we present our full research effort that has led to the synthesis of these molecules. Key aspects of our final strategy include 1) synthesis of the C1–C9 pyran core (5) using an AuCl3-catalysed cyclisation; 2) formation of C10–C22 vinyl iodide (55) by sequential bidirectional Stille reactions and 3) diastereoselective union of these advanced fragments by means of an alkenylzinc addition (d.r.=91:9 at C9). The common callipeltoside aglycon (4) was completed in a further five steps. Following this, all three sugar fragments were appended to provide the entire callipeltoside family. In addition to this, D-configured callipeltose B was synthesised and appended to the callipeltoside aglycon. The 1H NMR spectrum of this molecule was found to be significantly different to the natural isolate, further supporting our assignment of callipeltoside B (2).

Unprecedented Mechanism of an Organocatalytic Route to Conjugated Enynes with a Junction to Cyclic Nitronates

“…This was further corroborated by a modified experiment with DBU: Using a starting point with mainly 4a detectable and only traces of dimer 3a left, benzoic acid 15 was added leading to an increased amount of enyne (for data see SI). Subsequently, the reactive alt-1 probably rapidly interconverts to alt-2 through an [1,4]-H shift, which is followed by an intramolecular ring closure to alt-3 via the attack of the oxygen of the N-hydroxy-hydroxylamine releasing HNO 2 . Various 2D NMR experiments were used to assign the proton and carbon spin systems of this quite unusual intermediate (see Figure 3 and SI for spectra).…”

“…Dynemicin A, [1] Terbinafine [2,3] (Lamisil®), callipeltosides [4] or Neocarzinostatin [5] ], nitronates, especially cyclic nitronates, find application in the synthesis of biologically active compounds, [6,7] drug candidates [8][9][10] and natural products. While the structural motif of a conjugated enyne occurs in many pharmaceuticals and natural compounds [e.g.…”

Predicting Octanol–Water Partition Coefficients of Fluorinated Drug-Like Molecules: A Combined Experimental and Theoretical Study

“…The organic layer was washed with saturated NH 4 Cl solution 138.3 (ArC quat ), 128.4 (meta-ArC), 128.4 (para-ArC), 127.6 (ortho-ArC), 73.0 (PhCH 2 ), 69.2 (BnOCH 2 ), 41.0 (CH 2 CHO), 22.6 (CH 2 CH 2 CHO); spectroscopic data in accordance with literature values. [36] Step 2: A solution of 4-(benzyloxy)butanal (200 mg, 1.12 mmol) and (S)-a,a-bis[3,5-bis(trifluoromethyl)phenyl]-2-pyrrolidinemethanol trimethylsilyl ether [37] (6.5 mg, 0.011 mmol) in methyl tert-butyl ether (MTBE) (1.5 mL) was stirred at room temperature for 15 min. N-Fluorobenzenesulfonimide (NFSI) (233 mg, 0.748 mmol) was then added and the reaction mixture stirred at room temperature for 6 h. Pentane (6 mL) was then added and the white precipitate was filtered off.…”

Editorial

“…34 Two recent total syntheses of the immunosuppressant compounds antascomycin (Figure 4, b) 35 and (-)-rapamycin 36,37 (Figure 4, c) also illustrate the complexity involved in the construction of macrocyclic compounds. And the story goes on: for example this year, syntheses of the callipeltosides was reported, 38 illustrated by the structure of callipeltoside C (Figure 4, d).…”