Beak deprotonation

Dieter developed a flexible two step synthesis of substituted pyrroles involving initial Beak deprotonation of /ert-butoxycarbonyl (Boc) amines 36 followed by addition of CuX-2LiCl (X = -Cl, -CN) to afford a-aminoalkylcuprates. Such cuprates undergo conjugate addition reactions to a,(3-alkynyl ketones affording a,(3-enones 37, which upon treatment with PhOH/TMSCl undergo carbamate deprotection and intramolecular cyclization to afford the pyrroles 38 . 

A versatile activating group for the removal of a-protons that are not benzylic is the carbamate fert-butoxycarbonyl, or t-Boc group, developed for this purpose by Beak and Lee in 1989. Its utility derives from the fact that the Boc group is easy to attach to a secondary amine, and easy to remove after a deprotonation/alkylation sequence. Moreover, stannylation affords a-amino-organostannanes that are themselves useful precursors of a-amino-organolithium compounds (Scheme 29) (see Section II). In a chiral pyrrolidine system, it has been shown that both deprotonation (H Li) and methylation (Li Me) occur with retention of configuration. 

The chiral base i-BuLi/(—)-sparteine enantioselectively deprotonates the benzylic position of Ai-Boc-3-chloropropyl carbamates, which then cyclize to yield 2-substituted pyrrolidines with enantiomeric ratios greater than 90 10 (Scheme 63). Beak and coworkers showed that enantioselectivity is achieved through an asymmetric deprotonation to give an enantioenriched organolithium intermediate, which undergoes cyclization faster than epimerization. 

The first successful examples for asymmetric deprotonation by alkyllithium/(—)-sparte-ine (11) utilizing O-allyl and O-alkyl carbamates were published in 1989-1990 by Hoppe and coworkers °. Later, in 1991, Kerrick and Beak contributed the application of this method to Ai-Boc-pyrrolidine" (Sections II.D.l). 

As Beak and coworkers have established several years ago, A-rert-butoxycarbonyla-mines are sufficiently acidic to be deprotonated adjacent to the nitrogen atom . When applying 5-BuLi/(—(-sparteine (11) to A-Boc-pyrrolidine, asymmetric deprotonation (149), onepro-S-H is removed with high selectivity, furnishing the configurationally stable 2-lithio derivative 150 which was trapped with several electrophiles to form the optically active substitution products 151 (equation 33) A prescription in Organic Syntheses is... 

Bertini-Gross and Beak demonstrated in a broad study that conformationally restricted bicyclic carbamates undergo rapid diastereoselective deprotonation with s-BuLi/TMEDA". The proton closest to the carbonyl group is preferentially removed. Competition experiments gave information about the relative rates of deprotonation. Scheme 3 summarizes some second-order competitive efficiencies. 

Beak and coworkers accomplished the asymmetric deprotonation of several Ai-Boc-iV-(3-chloropropyl)arylmethylamines (240) with enantiomeric excesses up to 98 2 (equation 56). The intermediate lithium compound 241 cyclizes to form pyrrolidines 242 in good yields and enantioselectivities. The rapid intramolecular substitution step conserves the originally achieved high kinetic differentiation in the deprotonation step. 

Beak and coworkers found the (—)-sparteine-complex of iV-Boc-Af-(p-methoxyphe-nyl)benzyllithium 244, obtained from 243 by deprotonation with n-BuLi/(—)-sparteine (11) in toluene, to be configurationally stable (equation 57) . On trapping 244 with different electrophiles, the substitution products 245 are formed with high ee. Efficient addition reactions with imines and aldehydes have also been reported. The p-methoxyphenyl residue is conveniently removed by treatment with cerinm ammoninm nitrate (CAN). 

The asymmetric lithiation/substitution of Af-Boc-Af-(3-chloropropyl)-2-alkenylamines 395 by w-BuLi/(—)-sparteine (11) provides (5 )-Af-Boc-2-(alken-l-yl)pyrrolidines 397 via the allyllithium-sparteine complexes 396 (equation 106) . Similarly, the piperidine corresponding to 397 was obtained from the Af-(4-chlorobutyl)amine. Intramolecular epoxide openings gave rise to enantioenriched pyrrolidinols. Beak and coworkers conclude from further experiments that an asymmetric deprotonation takes place, but it is followed by a rapid epimerization a kinetic resolution in favour of the observed stereoisomer concludes the cyclization step. 

A kinetic resolntion by enantiodifferentiating deprotonation of atropoisomeric 1-naphthalenecarboxamides rac-436 by means of i-BuLi/(—)-sparteine (11) was reported by Thaynmanavan, Beak and Cnrran (equation 117). Compound (5 )-437 racemizes essentially completely during 8 d at room temperature. The stereoselectivity is achieved in the deprotonation step, as was demonstrated by control experiments. 

Whisler, M. C. McNeil, S. Snieckus, V. Beak, P. Beyond thermodynamic acidity a perspective on the complex-induced proximity effect in deprotonation reactions. Angew. Chem. Int. Ed. 2004, 43, 2206-2225. 

Computed properties of orotate derivatives other than the energetics of decarboxylation have also been published. The computed gas phase proton affinities of the 2- and 4-oxygens of orotate and of C6-deprotonated uracil have been reported by Lee and Houk to be 263 and 274 kcal mol-1, respectively, for orotate 02 and 04, and 285 and 302 kcal mol-1 for deprotonated uracil 02 and 04.16 The authors noted that the greater proton affinity of the 4-oxygen is relevant to the favorability of the 4-protonation pathway. Similar observations were made by Singleton, Beak and Lee and Phillips and Lee.46,47 Kollman and coworkers recently found that the most basic site of orotate appears to be C5, which is calculated to be 7 kcal mol-1 more basic than 04 at MP2/6-31 + G7/HF/6-31 + G. 27 This translates to a very low energy barrier for decarboxylation of the C5 protonated intermediate 10 kcal mol-1 at MP2/6-31 +G7/HF/6-31 + G, and 5 kcal mol-1 at MP2/cc-pVDZ. SCRF sol-... 

According to the the work of P. Beak and coworkers on 2-substituted pyrrolidines [2], the following synthetic route, containing asymmetric deprotonation and transformation of the protecting group, was chosen for the preparation of the (aminomethyl)silanes 3 and 5. The (aminomethyl)(lithiomethyl)silane 4, a molecule of type E (Scheme 1), was achieved by subsequent metalation of 3 (Scheme 2). 

The crucial reagents for the synthesis of the enantioemiched lithium compound (iS)-2 are (-)-sparteine complexes of simple alkyllithium bases. P. Beak and cowokers showed that f-BuLi and i-PrLi complexed by (-)-sparteine could be efficiently used for an asymmetric deprotonation reaction, whereas complexes of the chiral amine and t-BuLi or n-BuLi showed hardly any stereoselectivity or reactivity (Scheme 3) [2]. 

Dipole-Stabilization is a term coined by Beak to describe the situation that results when a carbanion is stabilized by an adjacent dipole. Such a situation arises when, for example, an amide is deprotonated a to nitrogen. The chemistry of these systems has been reviewed, - so only a few pertinent points will be made here. Firstly, metalation occurs syn to the carbonyl oxygen, and when the system is cyclic, the equatorial proton is removed selectively, and the electrophile attacks equatorially, as shown in equation (5), 24, 25 Thus, in contrast to nitrosamines, amide anions give the less stable equatorial product. 4,i25... 

Deprotonation of ethers is another route to the a-alkoxy anions, but this pathway is often precluded by a kinetic barrier. Unless the a-carbon is benzylic [175], surmounting this barrier usually requires conditions that are not favorable to the survival of the anion [164]. Notable exceptions are the hindered aryl esters studied by Beak [176], Figure 3.13a, and the carbamates studied by Hoppe [177], shown in Figure 3.13b. In both cases, ec-butyllithium is required for deprotonation, and the carbonyls which direct the metalation by a complex-induced proximity effect [178] must be shielded from the base by large alkyl groups. Once formed, the organo-lithiums are chelated and stabilized by the heteroatom-induced dipole [179]. 

Unlike lithiated tetrahydroisoquinolines, a-lithio derivatives of saturated heterocycles are configurationally stable [202-204] (review [163]), and they have a considerably higher kinetic barrier to deprotonation. Nevertheless, there have been a number of activating groups developed for the alkylation of a-lithio amines. In 1991, Beak showed that the complex of sparteine and sec-butyllithium enantioselectively deprotonates BOC-pyrrolidine, and that the derived organolithium is a good nucleophile for the reaction with several electrophiles, as shown in... 

An asymmetric deprotonation of (ferf-buto-xycarbonyl)pyrrolidines 25 has been recently developed by Beak allowing a highly enantioselective synthesis of a variety of 2-substituted pyrrolidines (Eq. 14). [21] Also amino-substituted benzylic lithiums have been generated with 5 BuLi (-)-3 and quenched stereo-selectively with electrophiles. [22]... 

Heteroatom-assisted metallation reactions are very common and especially useful for the selective o-functionalisation of aromatic compounds. More recently, activation of non-aromatic substrates has attracted attention but only a few examples pertinent to protecting groups will be cited here. Kerrick and Beak [Scheme 1.53] showed that pyrrolidine protected with a /err-butoxycarbonyl (Boc) group 53.1 is enantioselectively deprotonated by 5cc-BuLi activated by the alkaloid (-)-Sparteine (533). Enantioselective deprotonations mediated by (-)-Sparteine were first exploited by Hoppe and co-workers for the metallation of saturated and allylic - carbamates. 

---