No abstract

A concise synthesis of (+)-rishirilide B (2) is described. This is the first synthesis to be reported for the (+)-enantiomer of rishirilide B (2) as found in nature. The strategy accentuates the valuable combination of a method for o-quinone methide coupling with a method for enantioselective resorcinol dearomatization, which provides a densely functionalized chiral building block. The convergent synthesis illustrates several improvements and refinements to these methods and their supporting chemistries. Among these is the in situ generation of PhI[OTMS]OTf. Combination of this oxidant with phenol 31 constitutes the first example of a diastereoselective oxidative dearomatization of a resorcinol displaying a 2-alkyl substituent. In addition, the preparation of the cyclic sulfone 34 is reported. As a new dimethide precursor expressing a readily cleavable O-benzyl residue, sulfone 34 should prove useful in future endeavors. A protocol using the aluminum amide of dimethylhydrazine for opening and cleavage of a [1,4]-dioxan-2-one is also described. This procedure unmasks the hydroxy dione 36 by jettisoning the chiral directing group. Regioselective O-carbamylation of the 1,3-dione 36 enables the transformation of the remaining carbonyl into the α-hydroxy carboxylic acid found in 2. The total synthesis of (+)-rishirilide B (2) requires 15 pots from benzaldehyde 17 and 13 pots from benzaldehyde 32. The final product emerges in yields of 12.5% and 20.3% from compounds 17 and 32, respectively. The longest linear sequence requires eight chromatographies. Important observations leading to the development of the principle asymmetric method are described within the context of the total synthesis.

Syntheses of pyrazoles featuring a functionalized side chain attached to carbon 3 and varying alkyl and aryl substituents attached to carbon 5 are presented. Installation of R = methyl, isopropyl, tert-butyl, adamantyl, or phenyl groups at C5 is reported here, starting by coupling protected alkynols with acid chlorides RCOCl, forming alkynyl ketones, which are reacted with hydrazine to form the pyrazole nucleus. Alcohol deprotection and conversion to a chloride gave 5-substituted 3-(chloromethyl)- or 3-(2-chloroethyl)pyrazoles. This sequence can be done within 2 d on a 30 g scale in excellent overall yield. Through nucleophilic substitution reactions, the chlorides are useful precursors to other polyfunctional pyrazoles. In the work here, derivatives with side chains LCH(2)- and LCH(2)CH(2)- at C3 (L = thioether or phosphine) were made as ligands. The significance of the ligands made here is that by placing a ligating side chain on a ring carbon (C3), rather than on a ring nitrogen, the ring nitrogen not bound to the metal and its attached proton will be available for hydrogen bonding, depending on the steric environment created by R at C5.

Inter- and intramolecular hydrogen bonding of an N-H group in pyrazole complexes was studied using ligands with two different groups at pyrazole C-3 and C-5. At C-5, groups such as methyl, i-propyl, phenyl, or tert-butyl were present. At C-3, side chains L-CH(2)- and L-CH(2)CH(2)- (L = thioether or phosphine) ensured formation of chelates to a cis-dichloropalladium(II) fragment through side-chain atom L and the pyrazole nitrogen closest to the side chain. The significance of the ligands is that by placing a ligating side chain on a ring carbon (C-3), rather than on a ring nitrogen, the ring nitrogen not bound to the metal and its attached proton are available for hydrogen bonding. As desired, seven chelate complexes examined by X-ray diffraction all showed intramolecular hydrogen bonding between the pyrazole N-H and a chloride ligand in the cis position. In addition, however, intermolecular hydrogen bonding could be controlled by the substituent at C-5: complexes with either a methyl at C-5 or no substituent there showed significant intermolecular hydrogen bonding interactions, which were completely avoided by placing a tert-butyl group at C-5. The acidity of two complexes in acetonitrile solutions was estimated to be closer to that of pyridinium ion than those of imidazolium or triethylammonium ions.