Stereoselective lithiation

Guamieri, W. Sendzik, M. Frohlich, R. Hoppe, D. Regio- and stereoselective lithiation and C-substitution of (S)-2-(dibenzylamino)bu-tane-l,4-diol via dicarbamates. Synthesis 1998, 1274-1286. 

Ligands whose chirality is the result of atropisomerism, and not of an asymmetric center on phosphorus or carbon (Table 5), are highly enantioselective when complexed to Ru °. Heterobimetallic complexes form with metal-containing chiral ligands. Stereoselective lithiation of (S)- or (R)-a-ferrocenylethyldimethylamine (an easily resolved derivative of ferrocene) allows introduction of one or two phosphino groups, to need ferrocenylphosphinite (Table 6). ... 

A number of alternatives to oxazolines based on other diamine or amino alcohol derivatives have been proposed, and in several cases good control over planar stereoselectivity can be achievecL The earliest, published before any work on fer-rocenyloxazolines, drew on Nozaki s early studies [3,39] on stereoselective lithiation of aminomethylferrocenes, and made use of the proline-derived amino ether 45 (Scheme 13) [40]. Substitution of 44 gave 46, whose lithiation proceeded with 93 7 stereoselectivity with w-BuLi in ether at -78°C and with 99 1 stereoselectivity with s-BuIi in ether at -78°C. Reaction of 47 with ClPPh2 gave 48 the enantiomer is available by silylation, re-lithiation, phosphination and deprotection in the manner of Scheme 9. Removal of the prolinol auxihary is achieved by acetylation and hydrolysis to 49 [41]. 

Another noteworthy application of the Beak-O Brien chemistry is the stereoselective lithiation and carboxylation of a bicyclopyrrolidine 13 to access the bicycloproline 14, a key building block in the synthesis of the HCV protease inhibitor telaprevir 15 (Scheme 11.46). °... 

Morita, Y., Tokuyama. H.. and Fukuyama. T. (2005) Stereocontrolled total synthesis of (-)-kainic add. regio- and stereoselective lithiation of pyrrolidine ring with the (-l-)-sparteine surrogate. Org. Lett., 7, 4337-4340. 

This procedure illustrates a general method for the preparation of alkenes from the pal 1 adium(Q)-cata1yzed reaction of vinyl halides with organo-lithium compounds, which can be prepared by various methods, including direct regioselective lithiation of hydrocarbons. The method is simple and has been used to prepare a variety of alkenes stereoselectively. Similar stoichiometric organocopper reactions sometimes proceed in a nonstereoselective... 

The foregoing examples do not represent useful chiral formyl anion equivalents in a direct sense since the stereoselectivity of the initial addition to aldehydes is poor, although as has been explained, the situation is salvaged by oxidation and re-reduction. On the other hand, by lithiation at the 2 position of the achiral oxazo-lidine 53 in the presence of (-)-sparteine followed by addition of benzaldehyde, useful levels of d.e. and e.e. are achieved directly (98TA3125). For example, by adding MgBr2 before the benzaldehyde, the major product obtained is 54 in 80% d.e. and 86% e.e. 

Florio et al. demonstrated that the lithiation/electrophile trapping of enantio-pure styrene oxide, as well as the (3-substituted styrene oxides 180 and 182, is totally stereoselective (Scheme 5.42) [66]. These results demonstrate that the intermediate benzylic anions are configurationally stable within the timescale of depro-tonation/electrophile trapping. 

Pale et al. have reported that the stereoselective electrophile trapping of alkynyl-stabilized lithiated epoxides 189, generated from the parent epoxide 188 and n-BuLi, gives substituted epoxides such as 190, in good yield and de (Scheme 5.44) [67]. 

Uneyama et al. have shown that enantiopure trifluoromethyloxirane (193) can be lithiated and stereoselectively trapped with a variety of electrophiles to give substituted trifluoromethyloxiranes such as 195 (Scheme 5.46) [70] the use of a Weinreb amide as the electrophile is unusual. 

Lithiation/electrophile trapping of enantiopure epoxide 209 stereoselectively gave epoxide 211 further elaboration via a metalated epoxide gave spirocydic epoxide 212, which after treatment with acid gave epoxylactone 213 as a single dia-stereomer (Scheme 5.49) [74]. 

Seebach and coworkers examined the deprotonation/electrophile trapping of phe-nylthioaziridine carboxylates 236 (Scheme 5.58). These thioesters were found to be more stable than their oxy-ester congeners when lithiated treatment of 236 with LDA at -78 °C, followed by trapping with Mel at -100 °C, stereoselectively afforded aziridine 237 [83]. 

As well as for metalated epoxides, the trifluoromethyl moiety also proved an effective organyl-stabilizing group for metalated aziridines. Lithiated aziridine 241 reacted stereoselectively with carbonyl-containing electrophiles, and phenyl disulfide and chlorotrimethylsilane were also trapped in good yield (Scheme 5.60) [70b, 85],... 

Hodgson very recently reported an efficient intramolecular and completely dia-stereoselective cyclopropanation of bisliomoallylic and trisliomoallylic epoxides based on the use of a-lithiated epoxides. In a seminal paper, Crandall and Lin had reported that the reaction between t-BuLi and l,2-epoxyhex-5-ene (100) gave, inter alia, small amounts oftrans-bicyclo[3.1.0]hexan-2-ol (102, 9%) (Eq. a, Scheme 8.28)... 

However, addition of (+ )-(7 )-l-methyl-4-(mcthylsulfinyl)benzene, to aldehydes and ketones proceeds with low stereoselectivity. An improvement of the 3-syn diaslereoselectivity was found with the zinc reagent obtained by transmetalation of the lithiated sulfoxide with anhydrous zinc chloride38. An improvement of the stereoselectivity was also attained by exchange of the 4-methylphenyl substituent for a 2-methoxyphenyl or 2-pyridinyl substituent. Thus, the introduction of an additional complexing site into the aromatic part of the sulfoxide reagent enhances the stereoselectivity35. 

In another approach, a glucose-derived titanium enolate is used in order to accomplish stereoselective aldol additions. Again the chiral information lies in the metallic portion of the enolate. Thus, the lithiated /m-butyl acetate is transmetalated with chloro(cyclopentadienyl)bis(l,2 5,6-di-0-isopropylidene- -D-glucofuranos-3-0-yl)titanium (see Section I.3.4.2.2.I. and 1.3.4.2.2.2.). The titanium enolate 5 is reacted in situ with aldehydes to provide, after hydrolysis, /i-hydroxy-carboxylic acids with 90 95% ee and the chiral auxiliary reagent can be recovered76. 

The addition of lithium enolates to 2-alkoxyaldehydes occurs either in a completely non-stereoselective manner, or with moderate selectivity in favor of the product predicted by the Cram-Felkin-Anh model28 ( nonchelation control 3, see reference 28 for a survey of this type of addition to racemic aldehydes). Thus, a 1 1 mixture of the diastereomeric adducts results from the reaction of lithiated tert-butyl acetate and 2-benzyloxypropanal4,28. 

Lower stereoselectivities arise, however, from the addition of ester enolates to this glyceralde-hyde4. Another highly stereoselective addition is in the synthesis of erythromycin A where a single product results from the addition of lithiated tert-butyl thiopropanoate to the enantiomerically pure aldehyde (2/ ,3/ ,4,S, 6/ ,7/ ,8,S, 9/ ,10.S, 11 / )-7-acetoxy-3,4 9,10-bis(isopropy1-idenedioxy)-11-methoxymethoxy-2,4,6,8,10-pentamethyltridecanal5. 

The anomeric configuration is set in the reductive lithiation step, which proceeds via a radical intermediate. Hyperconjugative stabilization favors axial disposition of the intermediate radical, which after another single electron reduction leads to a configurationally stable a-alkoxylithium intermediate. Protonation thus provides the j9-anomer. The authors were unable to determine the stereoselectivity of the alkylation step, due to difficulty with isolation. However, deuterium labeling studies pointed to the intervention of an equatorially disposed a-alkoxylithium 7 (thermodynamically favored due to the reverse anomeric effect) which undergoes alkylation with retention of configuration (Eq. 2). 

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