The direct functionalization of C-H bonds in organic compounds has recently emerged as a powerful and ideal method for the formation of carbon-carbon and carbon-heteroatom bonds. This Review provides an overview of C-H bond functionalization strategies for the rapid synthesis of biologically active compounds such as natural products and pharmaceutical targets.

C-H bond functionalization: emerging synthetic tools for natural products and pharmaceuticals

Hydrogen bonds are like human beings in the sense that they exhibit typical grouplike behavior. As an individual they are feeble, easy to break, and sometimes hard to detect. However, when acting together they become much stronger and lean on each other. This phenomenon, which in scientific terms is called cooperativity, is based on the fact that 1+1 is more than 2. By using this principle, chemists have developed a wide variety of chemically stable structures that are based on the reversible formation of multiple hydrogen bonds. More than 20 years of fundamental studies on these phenomena have gradually developed into a new discipline within the field of organic synthesis, and is nowadays called noncovalent synthesis. This review describes noncovalent synthesis based on the reversible formation of multiple hydrogen bonds. Starting with a thorough description of what the hydrogen bond really is, it guides the reader through a variety of bimolecular and higher order assemblies and exemplifies the general principles that determine their stability. Special focus is given to reversible capsules based on hydrogen-bonding interactions that exhibit interesting encapsulation phenomena. Furthermore, the role of hydrogen-bond formation in self-replicating processes is actively discussed, and finally the review briefly summarizes the development of novel materials (nanotubes, liquid crystals, polymers, etc.) and principles (dynamic libraries) that recently have emanated from this intriguing field of research.

Noncovalent synthesis using hydrogen bonding

Alan Ford,† Hugues Miel, Aoife Ring,† Catherine N. Slattery,† Anita R. Maguire,*,†,‡ and M. Anthony McKervey* †Department of Chemistry and ‡School of Pharmacy, Analytical and Biological Chemistry Research Facility, Synthesis and Solid State Pharmaceutical Centre, University College Cork, Cork, Ireland Almac Discovery Ltd., David Keir Building, Stranmillis Road, Belfast BT9 5AG, United Kingdom Almac Sciences Ltd., Almac House, 20 Seagoe Industrial Estate, Craigavon BT63 5QD, United Kingdom

Modern Organic Synthesis with α-Diazocarbonyl Compounds

Transition metal chemistry of cyclopropenes and cyclopropanes.

Intellectual curiosity has always been one of the major driving forces leading to new advances in chemistry. At the onset of the 20th century, the fact that biaryls could be optically active even if lacking asymmetrically substituted carbon atoms arose interest, hinting at a novel type of stereomerism. It took quite a while (and some bizarre explanations)1 until in 1922 Christie and Kenner2 first correctly recognized that the phenomenon was the consequence of a hindered rotation about the aryl-aryl single bondshence termed atropisomerism by Kuhn. Still, no particular attention was initially paid to this class of stereoisomers until enantiomerically pure biaryls, such as BINAP (1),3 were found to be excellent ligands in asymmetric catalysis and until the chiral biaryl unit was recognized as the decisive structural element of many natural products (Figure 1).4,5 With the modern screening techniques and the bioassayguided search for novel compounds, the number of isolated axially chiral natural biaryls is steadily increasing.4 This class of secondary metabolites is characterized by a broad structural diversity, reaching from relatively simple molecules like the C2-symmetric biphenyl 2, which solely contains the element of axial chirality,6 to more complex compounds, like, e.g., the dimeric naphthylisoquinoline alkaloids michellamine A [(P,P)-3] and its axial epimer (i.e., its atropodiastereomer), michellamine B [(P,M)-3],7,8 which possess even three biaryl axes, of which the two outer ones are stereogenic, while * To whom correspondence should be addressed. E-mail: bringmann@ chemie.uni-wuerzburg.de; breuning@chemie.uni-wuerzburg.de. † These authors contributed equally to this work. ‡ Present address: Institute of Organic Chemistry, RWTH Aachen, Landoltweg 1, 52074 Aachen, Germany. § Present address: Kekulé Institute of Chemistry and Biochemistry, University of Bonn, Gerhard-Domagk Str. 1, 53121 Bonn, Germany. Gerhard Bringmann was born in 1951 and studied chemistry in Gie en and Münster, Germany. After his Ph.D. with Prof. B. Franck in 1978 and postdoctoral studies with Prof. Sir D. H. R. Barton in Gif-sur-Yvette (France), he passed his habilitation at the University of Münster in 1984. In 1986, he received offers for full professorships of Organic Chemistry at the Universities of Vienna and Würzburg, of which he accepted the latter in 1987. In 1998, he was offered the position of director at the Leibniz Institute of Plant Biochemistry in Halle, which he declined. His research interests focus on the field of analytical, synthetic, and computational natural product chemistry, i.e., on axially chiral biaryls. He received several prizes and awards, among them the Otto-Klung Award in chemistry (1988), the Prize for Good Teaching of the Free State of Bavaria (1999), the Adolf-Windaus Medal (2006), the Honorary Doctorate of the University of Kinshasa (2006), the Paul-J.-Scheuer Award (2007), and the Honorary Guest Professorship of Peking University (2008). Chem. Rev. 2011, 111, 563–639 563

Atroposelective total synthesis of axially chiral biaryl natural products.

Suzuki coupling of 7 to 8 gave the biphenyl derivative 9. Reaction of 9 with ethyl vinyl ether/bromine/base gave 10, which on treatment with CsF/DMF at 130 °C resulted in the cross-conjugated 2,5-cyclohexadienone 6. Acid hydrolysis of 6 gave 11, which was reductively aminated to give (±)-narwedine 2. Since 2 has been converted into (−)-galanthamine 1 in two steps, this synthesis proceeds in eight steps with an overall yield of 63%. Also treatment of the cross-conjugated cyclohexadienone 6 with nitromethane/base gave 12, which was reduced to provide 13. Reduction of the nitro group in 13 to an amine, followed by reductive amination under acidic conditions, arrives at the codeine skeleton 15. Elaboration of 15 into (±)-codeine proceeds via the previously unknown α-epoxide derivative 18. This is the shortest synthesis of codeine (13 steps, 20% overall yield) and, for the first time, allows access to codeine without having to reduce codeinone.

Concise syntheses of (-)-galanthamine and (+/-)-codeine via intramolecular alkylation of a phenol derivative.

Near infrared luminescence is observed in tetrametallic [Zn2Yb2L2(µ-OH)2Cl4]·2MeCN which is obtained from the Zn3 Schiff-base complex [Zn3L2(NO3)2]·MeOH, (H2L =
				N,N′-bis(5-bromo-3-methoxysalicylidene)propylene-1,3-diamine).

Synthesis and near infrared luminescence of a tetrametallic Zn2Yb2 architecture from a trinuclear Zn3L2 Schiff base complex

Synthesis of the Kopsia alkaloids (±)-pauciflorine B, (±)-lahadinine B, (±)-kopsidasine, (±)-kopsidasine-N-oxide, (±)-kopsijasminilam and (±)-11-methoxykopsilongine

During the course of studies on the synthesis of diazonamide A 1, an unusual O-aryl into C-aryl rearrangement was discovered that allows partial control of the absolute stereochemistry of the C-10 quaternary stereogenic center. Treatment of 30 with TBAF/THF gave the O-tyrosine ethers 31 and 32 (1:1), which on heating each separately in chloroform at reflux rearranged to 33 and 34 in ratios of 84:16 and 56:44, respectively. This corresponds to a 70% yield of the correct C-10 stereoisomer 33 and a 30% yield of the wrong C-10 stereoisomer 34. Attempts to convert 34 into 33 by ipso-protonation and equilibration were unsuccessful. Confirmation of the stereochemical outcome of the rearrangement was obtained by converting 33 into 37, an advanced intermediate in the first synthesis of diazonamide A by Nicolaou et al. It was also found that the success of the above rearrangement is sensitive to the protecting group on both the tryptophan nitrogen atom and the tyrosine nitrogen atom.

An expedient formal total synthesis of (-)-diazonamide A via a powerful, stereoselective O-aryl to C-aryl migration to form the C10 quaternary center.

The intramolecular addition of a diazo ester group to a triple bond in the presence of chiral dirhodium(II) carboxamidate catalysts gives macrocyclic lactones with a fused cycloproprene ring [Eq. (a)]. This efficient reaction is characterized by high enantiocontrol (up to 98% ee) and chemoselectivity.

Vince Lynch

Papers

Concise syntheses of (-)-galanthamine and (+/-)-codeine via intramolecular alkylation of a phenol derivative.

Synthesis and near infrared luminescence of a tetrametallic Zn2Yb2 architecture from a trinuclear Zn3L2 Schiff base complex

Synthesis of the Kopsia alkaloids (±)-pauciflorine B, (±)-lahadinine B, (±)-kopsidasine, (±)-kopsidasine-N-oxide, (±)-kopsijasminilam and (±)-11-methoxykopsilongine

An expedient formal total synthesis of (-)-diazonamide A via a powerful, stereoselective O-aryl to C-aryl migration to form the C10 quaternary center.

Macrocyclic Cyclopropenes by Highly Enantioselective Intramolecular Addition of Metal Carbenes to Alkynes.