Gem-dimethyls

Gemeprost (73 16.16-dimethvl-trans-A -prostaglandin-E]) is dramatically more potent on a dosage basis as an abortifacient than prostaglandin E2 itself and has fewer side effects. The gem-dimethyl groups at C-16 protect the alcohol moiety at C-15 from rapid metabolic oxidation. 

For oxathiane 1, lone pair selectivity is controlled by steric interactions of the gem-dimethyl group and an anomeric effect, which renders the equatorial lone pair less nucleophilic than the axial lone pair. Of the resulting ylide conformations, 25a will be strongly preferred and will react on the more open Re face, since the Si face is blocked by the gem-dimethyl group (Scheme 1.9) [3, 15]. 

The steric effect generated by the gem-dimethyl group of the thietane ring on the adjacent sp2 carbon atom makes the cycloaddition in these cases more sluggish compared with those of the parent thietane dioxide (6b)190. These cycloadditions provide a convenient entry into the strained thiabicyclo [2.2.0] hexane system (e.g. 287, 288 equation 107). 

In the case of y,6-unsaturated acids, five-membered rings (y-lactones) are predominantly formed (as shown above note that Markovnikov s rale is followed), but six-membered and even four-membered lactones have also been made by this procedure. There is a gem- dimethyl effect that favors formation of 7-11 membered ring lactones by this procedure. ... 

This general picture is similar to that observed in the ring-closing propensity of open chain alkanes, where a gem-dimethyl group greatly improves the yield of cycles as opposed to polymers (see 87, 88). This is known as the Thorpe-Ingold effect and has been examined in depth 1451. The steric bulk of the substituents diminishes the conformational space available for the open pre-... 

Selenium dioxide reveals a useful stereoselectivity when applied to trisubstituted gem-dimethyl alkenes. The products are predominantly the Zs-allylic alcohol or... 

Figure 18. A 0.2-s delayed COSY spectrum of the aliphatic region of 10 (2mg, CDCLj). Long-range "W-type" coupling of 19 and 21 axial protons to 30-CHj and coupling across the gem dimethyls from I9eq to 21 eq establish the position of oxidation at C-22. The spectrum was obtained under conditions similar to those in Figure 1, except that 32 transients were acquired for each of 128 x 512 data point spectra (17).

Catalyst Study. Equivalent amounts of p-phenylenebis(4,4-dimethyl-2-oxazol1n-5-one ) (2) and Jeffamine D-2000 (polyoxypropylenediamine from Texaco Chemical Co., amine equiv. weight 1023) were mixed with 5 mole % of the desired catalyst. The stirred mixture was heated at 240°C under argon for 30 minutes, then an additional 1.5 hours under vacuum (<1 torr) and collected. The amount of cyclization was estimated by 1H-NMR in CDC 13 by comparison of the Integrated intensities of the absorptions due to the gem-dimethyl substituents. These absorptions appeared at 1.39 ppm in the cyclic form and at 1.73 ppm in the open-chain form of the polymer (see Scheme 4). Results are listed in Table I. 

Spectra obtained by 1H NMR allowed the progress of the hydrogenolysis reaction to be followed quantitatively. The cyclopropyl protons in the polymer have an 1H NMR peak at 61.0 ppm, while the protons on the ring-opened, gem-dimethyl repeat unit (Equation A) have an XH NMR peak at 61.35 ppm. The gem-dimethyl peak assignment was based on chemical shift calculations (17). Also the dimethyl acetal of acetone has protons in a similar chemical environment to those on the gem-dimethyl ketal repeat unit and they have a chemical shift between 61.3 ppm and 61.A ppm (18). A proton NMR spectrum of partially hydrogenated polycyclopropanone is shown in Figure 7. 

Ni11 complexes with tri-, tetra-, penta-, and hexa-thia crowns have been studied.1675-1683 It has been shown that peripheral macrocycle modifications may lead to substantial improvements in Ni11 complexation gem-dimethyl substituents at the [14]ansS4 macrocycle (e.g., (659), (660))... 

Still another way to characterize metal surface sites by a chemical reaction is with the unique molecules (+)— and (—)—apopinene (Fig. 1.5).25-28 The apopinenes are an enantiomeric pair of molecules with a double bond steri-cally hindered on one side by a gem-dimethyl group. During hydrogenation, each enantiomer may hydrogenate to the saturated symmetrical apopinane or isomerize to its enantiomer, which will have the same reactivity on a symmetrical surface (Scheme 1.1). 

C1, C19, C26 pharmacophoric element C3, C11 transannular hydrogen bonding C7, C20 tunable substituents C8 gem-dimethyl crucial for bryostatin-like biological respose... 

The key step in the synthesis of A-ring fragment 50 [56] is the chelation-controlled addition of allylstannane 53 to aldehyde 52, which sets the C7 stereocenter and introduces the C8 gem-dimethyl moiety. Aldehyde 52 is itself prepared from 1,3-propanediol using the author s protocol for titanium-catalyzed enantioselective allylstannation [57], which sets the C5 stereocenter, followed by chelation-controlled Mukaiyama aldol addition [58] to establish the C3 stereocenter (Scheme 5.6). 

The two articles in this current volume describe recent developments with small ring compounds which have not teen compiled in such a context before. T. Hirao discusses selective transformations initiated by transition derivatives in the construction of functionally substituted five-, six- and seven-membered rings as well as open-chair compounds. Cycloadditions onto methylene- and alkylidene-cyclopropane derivatives, described by A. Goti, F. M. Cordero and A. Brandi, not only yield products with spirocyclopropane moieties which can be desirable as such or as potential mimics of gem-dimethyl groupings, but also intermediates which can undergo further transformations with ring-opening of the cyclopropane units. 

Had the compound been less stable than we would predict the discrepancy would have been easier to explain. One could argue that the gem- dimethyl groups would have resulted in destabilization because of buttressing . It is tempting to argue that the triene was contaminated by polymer and/or peroxide, both of which have lower enthalpies of formation. But we have no documentation of this. 

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