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. 2009 Aug 21;74(16):6169-80.
doi: 10.1021/jo901073v.

Development of an automated microfluidic reaction platform for multidimensional screening: reaction discovery employing bicyclo[3.2.1]octanoid scaffolds

John R Goodell  1 , Jonathan P McMullen, Nikolay Zaborenko, Jason R Maloney, Chuan-Xing Ho, Klavs F Jensen, John A Porco Jr, Aaron B Beeler
Affiliations

Development of an automated microfluidic reaction platform for multidimensional screening: reaction discovery employing bicyclo[3.2.1]octanoid scaffolds

John R Goodell et al. J Org Chem. .

Abstract

An automated, silicon-based microreactor system has been developed for rapid, low-volume, multidimensional reaction screening. Use of the microfluidic platform to identify transformations of densely functionalized bicyclo[3.2.1]octanoid scaffolds will be described.

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Figures

Figure 1
Figure 1
Diverse functionality of the bicyclo[3.2.1]octanoid scaffold for multidimensional reaction screening.
Figure 2
Figure 2
Automated microfluidic platform for reaction screening. Components include: (a) computer with operating software, (b) multi-head syringe pump, (c) liquid handler, (d) 96-well reagent block, (e) compression packaging that houses microreactor and thermoelectric module, (f) UV detection for optical triggering, (g) sampling valve, (h) 96-well plate fraction collector, and feedback control loops (i – k) for reagent injection, temperature control, and sample collection, respectively.
Figure 3
Figure 3
Reagent storage block (left) and illustration of inert handling in sample syringes (right).
Figure 4
Figure 4
a) Illustration of sequential reaction pluses and the dispersion caused by laminar flow and surface wetting. b) Example of sample collection via optical triggering. Collection begins and terminates once concentration of reaction pulse crosses a specified threshold, thereby enabling collection of the central portion of the pulse.
Figure 5
Figure 5
Layout of the silicon microreactor used for multidimensional screens.
Figure 6
Figure 6
Compression packaging unit used in screening applications. The unit houses microreactor and thermoelectric device used for heating/cooling.
Figure 7
Figure 7
Multidimensional screening parameters.
Figure 8
Figure 8
UPLC/ELSD results for successful transformations with bicyclo[3.2.1] substrate 7. The shaded region represents the LC retention time for bicyclo[3.2.1] substrate 7. Reaction conditions for displayed traces: DMSO, TBD, 5 min, 30 °C.
Figure 9
Figure 9
UPLC/ELSD results for successful transformations with bicyclo[3.2.1] substrate 9. The shaded area represents the LC retention time for bicyclo[3.2.1] substrate 9. Reaction conditions for displayed traces: CH3CN, TBD, 5 min, 30 °C.
Scheme 1
Scheme 1
Synthesis of bicyclo[3.2.1]octanoid scaffolds.
Scheme 2
Scheme 2
Further cyclization of allyl Grignard adducts.
Scheme 3
Scheme 3
Representative products for isonitrile reactions.
Scheme 4
Scheme 4
Condensation with an isonitrile ylide affords a polycyclic imine.
Scheme 5
Scheme 5
Proposed mechanism for the formation of polycyclic imine 113.
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