Exploration of a Au(i)-mediated three-component reaction for the synthesis of DNA-tagged highly substituted spiroheterocycles

Abstract

We demonstrate a Au(i)-mediated three-component reaction to DNA-tagged highly substituted 6-oxa-1,2-diazaspiro[4.4]nonanes from either DNA-coupled aldehydes, hydrazides, or alkynols. The choice of the starting material coupled to the DNA tag was critial for the purity of the product as the DNA-aldehyde conjugate yielded the purest products, whereas the alkynol- and hydrazide conjugates returned complex product mixtures. The reaction was compatible with thymine-, cytosine-, and, surprisingly, with adenine-DNA, while guanine-containing DNA strands were degraded under the reaction conditions.

Synthesis of Macrocycles Derived from Substituted Triazines

“…Compositional differences between 1 and 2 rest on the choice of alkyl group on the hydrazine residue. N ‐Isopropyl‐ N′ ‐BOC‐hydrazine (for 1 ) and N ‐benzyl‐ N′ ‐BOC‐hydrazine (for 2 ) were prepared starting with tert ‐butyl carbazate. Following 12 hours′ incubation with an excess of either acetone or benzaldehyde in ether at room temperature, the solvent was removed.…”

“…tert ‐Butyl‐2‐benzylidenehydrazine‐1‐carboxylate : The procedure follows a known synthesis . NaBH 3 CN (2.82 g, 44.9 mmol) was slowly added to a stirred solution of tert ‐butyl‐2‐benzylidenehydrazone‐1‐carboxylate (4.00 g, 18.0 mmol) in dry THF (40 mL) at 0 °C.…”

“…tert ‐Butyl 2‐isopropylhydrazinecarboxylate : The procedure follows a known synthesis . NaBH 3 CN (1.47 g, 23.2 mmol) and catalytic bromocresol green were added to a stirred solution of tert ‐butyl 2‐isopropylhydrazonecarboxylate (4.00 g, 23.2 mmol) in dry THF (150 mL), then a solution of p ‐toluenesulfonic acid (4.41 g, 23.2 mmol) in dry THF (12 mL) was added dropwise over 1 h. The reaction mixture was maintained between pH 3.5–5.0.…”

Chemisch stabilisierte DNA‐Codes für DNA‐kodierte Chemie

“…Dies wird durch die Beobachtung unterstützt, dass elektronenreiche Hydrazine die chemisch stabilisierte DNA stärker schädigten (bis zu 50 %, Tabelle S14). Au I ‐vermittelte Pyrazolin‐ oder Pyrazol‐Synthesen wurden kaum von nativer DNA toleriert (Abbildung 3 O–Q) [15, 25] . Die Au I ‐vermittelte Reaktion des 16mer 7De‐dATC‐Aldehydkonjugats 13 mit Alkinol 49 und Hydrazid 50 zu einem Spiroheterocyclus lief jedoch reibungslos mit 59 % Umsetzung ab (Abbildung 3 O).…”

Chemically Stabilized DNA Barcodes for DNA‐Encoded Chemistry

“…This is supported by the observation that electron‐rich hydrazines caused higher levels of DNA damage (up to 50 %) even to the stabilized DNA barcode (Table S14). Au I ‐mediated pyrazoline[ 15 , 25 ] or pyrazole [15] syntheses caused high degrees of damage to native DNA (Figure 3 O –Q). However, the Au I ‐mediated reaction of 16mer 7De‐dATC aldehyde conjugate 13 with alkynol 49 and hydrazide 50 towards a spiroheterocycle worked smoothly with 59 % conversion (Figure 3 O ).…”