Abstract
Short aliphatic groups are prevalent in bioactive small molecules and play an essential role in regulating physicochemistry and molecular recognition phenomena. Delineating their biological origins and significance have resulted in landmark developments in synthetic organic chemistry: Arigoni's venerable synthesis of the chiral methyl group is a personal favourite. Whilst radioisotopes allow the steric footprint of the native group to be preserved, this strategy was never intended for therapeutic chemotype development. In contrast, leveraging H → F bioisosterism provides scope to complement the chiral, radioactive bioisostere portfolio and to reach unexplored areas of chiral chemical space for small molecule drug discovery. Accelerated by advances in I(i)/I(iii) catalysis, the current arsenal of achiral 2D and 3D drug discovery modules is rapidly expanding to include chiral units with unprecedented topologies and van der Waals volumes. This Perspective surveys key developments in the design and synthesis of short multivicinal fluoroalkanes under the auspices of main group catalysis paradigms.
Highlights
IntroductionFocussed molecular design strategies[5] with short per uoroalkyl groups such as CF3 and CF(CF3)[2] enjoying “privileged” status.[6,7] In a reductionist sense, the functional diversity of uorinated materials can be attributed to the physicochemical consequences of C(sp2/sp3)-Hd+ / C(sp2/sp3)-FdÀ structural editing[8] and the new regions of chemical space that result.[9]
Short aliphatic groups are prevalent in bioactive small molecules and play an essential role in regulating physicochemistry and molecular recognition phenomena
Delineating their biological origins and significance have resulted in landmark developments in synthetic organic chemistry: Arigoni's venerable synthesis of the chiral methyl group is a personal favourite
Summary
Focussed molecular design strategies[5] with short per uoroalkyl groups such as CF3 and CF(CF3)[2] enjoying “privileged” status.[6,7] In a reductionist sense, the functional diversity of uorinated materials can be attributed to the physicochemical consequences of C(sp2/sp3)-Hd+ / C(sp2/sp3)-FdÀ structural editing[8] and the new regions of chemical space that result.[9]. Stephanie Meyer was born in Sogel (Germany) in 1995 She completed her Bachelors degree in chemistry at the WWU Munster, which included an internship with Prof. Andrei Yudin's group at the University of Toronto as a visiting student (Canada, 2018). Stephanie completed her Masters degree working with Prof. Ryan Gilmour (2019) and remained in the group as a doctoral student working on I(I)/I(III) catalysis. Joel Ha iger was born in Willisau (Switzerland) in 1995 He completed his undergraduate studies in chemistry at the ETH Zurich where he worked with Prof. His current work is focussed on the application and development of novel iodine(I)/(III) catalysed uorination processes. This personal Perspective re ects on the possible motivating factors that have led to a surge of interest in the generation of short, chiral uorinated groups and highlights the important role of I(I)/I(III) catalysis as an enabling technology in this arena
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