Synlett 2016; 27(02): 262-266
DOI: 10.1055/s-0035-1560644
letter
© Georg Thieme Verlag Stuttgart · New York

An Orthogonal Biocatalytic Approach for the Safe Generation and Use of HCN in a Multistep Continuous Preparation of Chiral O-Acetylcyanohydrins

Aischarya Brahma
a  IBG-1: Biotechnology, Forschungszentrum Jülich, 52425 Jülich, Germany
b  Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW, UK   Email: svl1000@cam.ac.uk
,
Biagia Musio
b  Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW, UK   Email: svl1000@cam.ac.uk
,
Uliviya Ismayilova
c  Institute of Nano- and Biotechnologies (INB), Aachen University of Applied Sciences, 52428 Jülich, Germany
,
Nikzad Nikbin
b  Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW, UK   Email: svl1000@cam.ac.uk
,
Sonja B. Kamptmann
b  Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW, UK   Email: svl1000@cam.ac.uk
,
Petra Siegert
c  Institute of Nano- and Biotechnologies (INB), Aachen University of Applied Sciences, 52428 Jülich, Germany
,
Günter E. Jeromin
c  Institute of Nano- and Biotechnologies (INB), Aachen University of Applied Sciences, 52428 Jülich, Germany
,
Steven V. Ley*
b  Department of Chemistry, University of Cambridge, Cambridge, CB2 1EW, UK   Email: svl1000@cam.ac.uk
,
Martina Pohl
a  IBG-1: Biotechnology, Forschungszentrum Jülich, 52425 Jülich, Germany
› Author Affiliations
Further Information

Publication History

Received: 03 August 2015

Accepted after revision: 03 September 2015

Publication Date:
29 September 2015 (online)


Abstract

An enantioselective preparation of O-acetylcyanohydrins has been accomplished by a three-step telescoped continuous process. The modular components enabled an accurate control of two sequential biotransformations, safe handling of an in situ generated hazardous gas, and in-line stabilization of products. This method proved to be advantageous over the batch protocols in terms of reaction time (40 min vs 345 min) and ease of operation, opening up access to reactions which have often been neglected due to safety concerns.

Supporting Information

 
  • References and Notes

  • 1 These authors did the main part of the experiments and contributed equally. The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.
  • 2 Present address: Novartis Pharma, AG WSJ-42.2.08, 4002 Basel, Switzerland.
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    • General procedure for the three-step cascade synthesis of chiral O-acetylcyanohydrins in flow: A 1 M solution of ECF in microaqueous MTBE was pumped (0.04 mL/min) into a 10 cm packed-bed reactor containing CalB (277 mg). This first output, consisting of 1 M solution of HCN, was mixed with a 0.5 M solution of aldehyde 1af in micro-aqueous MTBE (0.04 mL/min–1) by means of a tee piece assembly. The resulting mixture was passed through a second bioreactor (Kinesis, Benchmark microbore column 3 mm/100 mm 2 × F), containing lyophilized E. coli-AtHNL- (250 mg), prepared as described in the SI (section S5). A back pressure regulator (5 Bar) was introduced after the packed bed reactor. The out coming solution was mixed with a mixture of pyridine/acetic anhydride (1:1) pumped by a compact HPLC pump (Knauer) and the resulting solution was passed through a PTFE coil (2 mL). The layers were collected and a sample (50 μL in 500 μL of CDCl3) was analyzed by NMR to check the formation of (R)-3a, (R)-3b, (R)-3c, (R)-3d, (S)-3e and (R)-3f (75–99%). The optical purity of the products (40–98%) was assessed by GC analysis. CAUTION: special precautions must be taken because the HCN is highly toxic. All work was carried in a well ventilated fumehood and a gas monitor for HCN was used during all the stages of the experiments. The excess of HCN (1 eq) was treated with an aqueous solution of sodium hypochlorite (10–15%) until neutralization. The spectroscopic data of compounds 3af are in accordance with literature:
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