The solid-phase combinatorial synthesis of cyclodepsipeptide destruxin E has been demonstrated. The combinatorial synthesis of cyclization precursors 8 was achieved by using a split and pool method on SynPhase Lanterns. The products were successfully macrolactonized in parallel in the solution phase by using 2-methyl-6-nitrobenzoic anhydride and 4-(dimethylamino)pyridine N-oxide to afford macrolactones 9, and the subsequent formation of an epoxide in the side chain gave 18 member destruxin E analogues 6. Biological evaluation of analogues 6 indicated that the N-MeAla residue was crucial to the induction of morphological changes in osteoclast-like multinuclear cells (OCLs). Based on structure–activity relationships, azido-containing analogues 15 were then designed for use as a molecular probe. The synthesis and biological evaluation of analogues 15 revealed that 15 b, in which the Ile residue was replaced with a Lys(N₃) residue, induced morphological changes in OCLs at a sufficient concentration, and modification around the Ile residue would be tolerated for attachment of a chemical tag toward the target identification of destruxin E (1).

The total synthesis and stereochemical structural elucidation of JBIR-39, containing four nonproteinogenic piperazic acid (Piz) residues, is reported. The synthesis includes Sc(OTf)₃-catalyzed acylation of a Piz(γ-OTBS) derivative with piperazic acid chloride, providing the desired Piz-Piz(γ-OTBS) dipeptide in high yield without epimerization. After assembling two additional Piz moieties and (S)-isoleucic acid at the N-terminus, amidation with the (R)-α-methylserine ester at the C-terminus, and deprotection afforded the desired (2R,8S)-hexapeptide, which is the assumed structure of JBIR-39. Although the spectral data of the (2R,8S)-hexapeptide was not identical to JBIR-39, further synthesis of three stereoisomers confirmed the stereochemical structure of JBIR-39 to be (2S,6S,8S,11R,16S,21R,26S,27S).

The partial reduction of α,β-unsaturated esters and benzoate derivatives to form the corresponding aldehydes was achieved using a flow reactor system within 1 s at a high flow rate (18 mL min^–1) under cryogenic conditions (–97 °C). Commercially available diisobutylaluminium hydride (DIBAL-H) was used as the reductant. The desired enals and benzaldehyde derivatives, except for 4-methoxycinnamate and 4-methoxybenzoate, were formed selectively and redox economically in moderate to high yields.

Two approaches for the solid-phase total synthesis of apratoxin A and its derivatives were accomplished. In synthetic route A, the peptide was prepared by the sequential coupling of the corresponding amino acids on trityl chloride SynPhase Lanterns. After cleavage from the polymer-support, macrolactamization of 10, followed by thiazoline formation, provided apratoxin A. This approach, however, resulted in low yield because the chemoselectivity was not sufficient for the formation of the thiazoline ring though its analogue 33 was obtained. However, in synthetic route B, a cyclization precursor was prepared by solid-phase peptide synthesis by using amino acids 13–15 and 18. The final macrolactamization was performed in solution to provide apratoxin A in high overall yield. This method was then successfully applied to the synthesis of apratoxin analogues. The cytotoxic activity of the synthetic derivatives was then evaluated. The epimer 34 was as potent as apratoxin A, and O-methyl tyrosine can be replaced by 7-azidoheptyl tyrosine without loss of activity. The 1,3-dipolar cycloaddition of 38 with phenylacetylene was performed in the presence of a copper catalyst without affecting the thiazoline ring.

Catalytic activities of NHC-derived nickel–pincer complexes for the Suzuki–Miyaura coupling reactions of aryl/alkenyl tosylates and mesylates are described. In the presence of a catalytic amount of nickelacycle 1a, a wide array of tosylates and mesylates reacted with several aryl- and alkenylboronic acids to afford the coupling products, generally in high yields. Fine tuning of the reaction conditions for each class of electrophiles was achieved only by choosing the appropriate reaction medium (DME for tosylates, dioxane for mesylates).(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)