Synthesis of (±)-phthalascidin 650 analogue: new synthetic route to (±)-phthalascidin 622

A synthesis of functionalized phenolic α-amino-alcohol (±)-13 as synthetic precursor of the catechol tetrahydroisoquinoline structure of phthalascidin 650 is disclosed. Starting from 3-methylcatechol 5, eight steps of synthesis give rise to the synthesis of phenolic α-amino-alcohol (±)-13 in 27% overall yield. This synthetic strategy involves the elaboration of fully functionalized aromatic aldehyde 8 and its transformation into a phenolic α-amino-alcohol (±)-13, through a Knoevenagel condensation, simultaneous reduction of nitroketene and ester functions and hydrogenolysis of the benzyl protecting group. The pentacycle (±)-18 was obtained after four additional steps. The Pictet-Spengler cyclisation between the phenolic α-amino-alcohol (±)-13 and N-protected α-amino-aldehyde 4 allowed to obtain (1,3′)-bis-tetrahydroisoquinoline 14 with N-methylated and N-Fmoc removed. The last step was a Swern oxidation for allowing an intramolecular condensation.     

Effects of microchannel geometry on pulsed flow mixing

Although the mixing of reagents is often crucial in many microfluidic devices, good mixing in these laminar, low Reynolds number, flows remains a challenge. It was shown in Refs. [Glasgow, I., Aubry, N., 2003. Lab on a Chip 3, p. 114; Glasgow, I., Batton, J., Aubry, N., 2004. Lab on a Chip 4, p. 558] that pulsing can induce mixing at the confluence of two inlet microchannels in an efficient manner. In this paper, we show that this mixing is affected by both the geometry of the confluence and the inclusion of features in the channels, which induce secondary flow. More specifically, we study mixing in 200 μm wide by 120 μm deep channels, at flow rates from 48 nl s⁻¹ to 4.8 μl s⁻¹, corresponding to Reynolds numbers of 0.3–30. For the parameter values studied, the pulsed flow technique is more effective at mixing than the secondary flow induced by the channel geometry features, and combining both methods leads to even better mixing. In addition, pulsing the reagents such that they pass multiple times through the spatial features, which induce secondary flow leads to mixing over shorter distances.