Both the arrest and thecreationofmovement are fundamental aspects of dynamics on macroscopic as well as microscopic levels. Brakes and motors dominate the operation of machines, be they those of daily life, such as vehicles and appliances, or those of living systems. like muscles and Ilagellae. On the molecular level motion is thenorm;spontanwus freerotationaroundsinglebonds is thus the rule, not the exception. In machines of ordinary experience, such as automobiles, the brake is often as important as the accelerator. We now report the first molecular analog: a reversible molecular brake. Figure I presents theconcept inbothgeneral andspecific terms. 1 (biako ofl) 3 (brako on) -"W 2 (brake ott) 4 (brake on) Figure 1. Conceptualandaetualdepictionoftheoperationofa molecular brake. With the brakedisengaged. the wheel-(a) representedasa threetoothed gear ( I ) and (b) constructed as a triptycene (2)' -spins rapidly. Engagement ofthe brake (3and4) slowsorstopsrotation. With the actual system, the brake is activated remotely (2 -4) by addition of Hg2+ ion. In the absence of Hgz+ (or other metal ions), the triptycene wheel spins rapidly a t 30 OC, as evidenced by the simplicity of the 'H NMR spectrum of 2 (Figure 2b). wherein by virtue of C, symmetry arising from relatively rapid rotation, the 12 triptycene aromatic protons give rise to only four sets (asterisked) of resonances. Addition of Hg(OzCCF3)z to 2 results in profound changes in the 30 OC (and other) 'H NMR spectrum (Figure 3a). Most noteworthy are the change in the extraordinarychemicalshiftoftheB-ringmethoxyin 2 (6 2.1 to a normal 6 4. I 3 value (not shown) and the obvious broadening of the four resonances attributable to the hydrogens in the three benzo rings of the triptycene. Variable-temperature 'H NMR experiments3 (see Figure 3) document the engagement of the brake. In particular, a t -30 OC (contrast Figure 2),thethreearomaticringsofthetriptyceneare nolongerequivalent becauseofthearrest ofrotation on theNMR . . ( I ) For the use of triptycenaas gean see, inter alia (a) Guenzi. A,: Johnson. C.(2) The 9-ring mcthary group is evidently (see models) in the shielding zone of the lriplycene knzo rings; the B-ring melhory group in 9 is similarly shielded (6 2.W).'(3) See supplementary material for specifis.

No abstract

An efficient synthesis of a structurally unique, novel M(3) antagonist 1 is described. Compound 1 is conveniently disconnected retrosynthetically at the amide bond to reveal the acid portion 2 and the amine fragment 3. The synthesis of key intermediate 2 is highlighted by a ZnCl(2)-MAEP complex 19 catalyzed diastereoselective Michael reaction of dioxolane 7 with 2-cyclopenten-1-one (5) to establish the contiguous quaternary-tertiary chiral centers and a subsequent geminal difluorination of ketone 17 using Deoxofluor in the presence of catalytic BF(3).OEt(2). The synthesis of the amine moiety 3 is highlighted by the discovery of a novel n-Bu(3)MgLi magnesium-halogen exchange reaction for selective functionalization of 2,6-dibromopyridine. This new and practical metalation protocol obviated cryogenic conditions and upon quenching with DMF gave 6-bromo-2-formylpyridine (26) in excellent yield. Further transformations afforded the amine fragment 3 via reductive amination with 35, Pd-catalyzed aromatic amination, and deprotection. Finally, the highly convergent synthesis of 1 was accomplished by coupling of the two fragments. This synthesis has been used to prepare multi-kilogram quantities of the bulk drug.

Dimethyl sulfomycinamate (1), a methanolysis product from the natural antibiotic sulfomycin I, is synthesized in 11 steps (Scheme 19). The chemistry of various pyridine, thiazole, and oxazole heterocycles and their coupling reactions under palladium catalysis are examined. The key transformations in the synthesis are the selective palladium-catalyzed coupling reactions on doubly activated pyridine 62 and the condensation reaction between bromo ketone 69 and amide 28 to form the oxazole moiety 76. The first preparation of oxazole triflates is described, as are some of their chemical properties.

A convergent total synthesis of the anti-HIV michellamines (1) is described. The tetraaryl skeleton of the michellamines was constructed by formation first of the inner (nonstereogenic) biaryl axis and subsequently of the two other (stereogenic) axes in a highly convergent manner. The key transformation features a double Suzuki-type cross-coupling reaction between binaphthalene ditriflate 26 and isoquinolineboronic acid 35. Ditriflate 26 is synthesized in six steps starting from diene 6 and 2,6-dibromobenzoquinone (9) in 21% overall yield. For large scale production of 26, a substantially shortened version of an existing procedure for the preparation of bisnaphthoquinone 13 was also developed, which allows for the preparation of 13 from benzoquinone and diene 6 in five steps and 67% overall yield. Binaphthoquinone 13 was subsequently converted into ditriflate 26 in three steps and 67% overall yield. By the described synthetic strategy, michellamines A (1a) and B (1b) are produced (1a:1b = 1:2.5) in 24.6% overall yield from diene 6. Curiously, none of the nonnaturally occurring atropoisomer 1c is formed.