Current Organic Chemistry, 2003, 7, 867-926 867 Functionalized Organolithium Compounds: New Synthetic Adventures Carmen Nájera* and Miguel Yus* Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain Abstract: This review covers literature on non-stabilized functionalized organolithium compounds since 1997. In this overview, we consider intermediates with different separation between the functional group and the carbon- lithium bond (dn-reagents) and having different hybridization at the carbanionic centre. Special emphasis is given to the synthetic applications of these intermediates in order to prepare polyfunctionalized molecules. 1. GENERAL INTRODUCTION 2. a- FUNCTIONALIZED ORGANOLITHIUM COM- POUNDS The use of carbanions as intermediates is a milestone in synthetic organic chemistry. Organometallic compounds are This type of non-stabilized reagents can bear oxygenated used for the formation of all kind of hybridized carbon- or nitrogenated functionalities at the a -position, either with carbon bonds. The more polar organolithium compounds sp3 or sp2 hybridization, mainly in acyclic (1 and 3) or cyclic provide excellent electrophilic reactivity and are probably systems (2 and 4). the most popular organometallics in contemporary organic chemistry [1]. Functionalized organolithium compounds are specially useful in order to transfer a functionality in only a synthetic operation [2]. However, obviously the functional group has to be compatible with the carbon-lithium bond. For this reason, the functionality should be protected and the organolithium reagent has to be prepared at low temperatures and in many cases in the presence of the electrophile 3 (Barbier-type conditions) [3]. The preparation of organo- 2.1. sp -Hybridized a -Oxygenated Organolithium Com- lithium compounds is based on (a) deprotonation with pounds lithiated bases [4], (b) halogen-lithium exchange, (c) trans- metallation reactions, mainly tin-lithium exchange, (d) Functionalized alkyllithiums 1 bearing an oxygen at the carbon-heteroatom bond cleavage, and (e) carbolithiations a -position can be generated by chlorine-lithium or tin- [5]. lithium exchange, as well as by a -deprotonation in the case of activated allylic or benzylic systems. Intermediate 6, The stability of functionalized organolithium compounds derived from chloromethyl ethyl ether 5, was prepared by depends on the location and the nature of the functionality means of lithium powder and either di-tert-butylbiphenyl (or the heteroatom), the hybridization of the carbon bonded (DTBB; 5 mol%) [7], or naphthalene- (PN) as well as to the metal and their aggregation. biphenyl-supported (PB) polymers [8], working either in a two-step process or under Barbier-type reaction conditions This review article deals comprehensively with the (Scheme 1). literature published from 1997, and it is the third part of our previous revisions [2a,b]. Stabilized organolithium com- pounds by electron-withdrawing groups or by heteroatoms such as sulfur, selenium, phosphorous, or silicon, as well as acyllithium or functionalized aryllithium compounds will be not consider. This revision is ordered considering both, the relative position of the heteroatom (or the functional group) respect Scheme 1. Reagents: i, Li, DTBB (5 mol%), –90ºC; ii, E = RCHO, to the carbanionic centre and its hybridization. R2CO, CO2, PhCN, PhCONMe2, CyNCO, PhN=CHPh; iii, H2O. Chiral lithiomethyl ethers 8-9 bearing the menthol unit were also prepared by chlorine-lithium exchange from the corresponding chloromethyl menthyl ethers. The metallation can be carried out with lithium powder and DTBB (5 mol%) *Address correspondence to this author at the Departamento de Química in THF at 0ºC in the presence of carbonyl compounds, Orgánica, Facultad de Ciencias, Universidad de Alicante, Apdo. 99, 03080 Alicante, Spain; Tel: (+34) 965 903548; Fax: (+34) 965 903549; E-mail: imines, DMF and Me3SiCl as electrophiles. For the two-step [email protected]; [email protected] process, the lithiation has to be carried out at –90ºC, followed by addition of the corresponding electrophile at the 1385-2728/03 $41.00+.00 © 2003 Bentham Science Publishers Ltd. 868 Current Organic Chemistry, 2003, Vol. 7, No. 9 Najera and Yus Scheme 2. Reagents: i, BuLi (2 equiv), 30% THF/Et2O, –78ºC; ii, Scheme 3. Reagents: i, BuLi, THF, –78ºC; ii, E = MeOD, D2O, PhCHO; iii, CSA, MeOH, rt. RCHO, Me2CO, DMF, MeI; iii, H2O. same temperature. When prochiral electrophiles are used, low asymmetric induction was obtained (up to 1:2) [9]. Intermediates ent-8, 9 and 10 were also prepared by tin- lithium exchange and gave similar level of asymmetric induction [10]. A chiral derivative of tributylstannylmethanol 11, Scheme 4. Reagents: i, Li, DTBB (2.5 mol%), E = RCHO, prepared from L-valine, provided after tin-lithium exchange R1R2CHO, Me SiCl, THF, –78ºC; ii, H O. a a -alkoxy organolithium compound 12 (Scheme 2). This 3 2 chiral alkoxymethyl carbanion added to benzaldehyde with clean reactions to yield products 20 with retention of the up to 91:9 diastereomeric ratio, depending on the solvent and configuration and with 2.6:1 dr in the case of benzaldehyde the alkyllithium used for the transmetallation. Better results [12]. were obtained with 30% THF in ether providing the diol 13 in 91% yield and 88:12 er. Final hydrolysis of the adducts O-Chloroalkyl carbamates 21 were transformed into the allowed the synthesis of 1,2-diols 13 and the recovery of the corresponding dipole-stabilized lithiated species by DTBB- chiral auxiliary 14 [11]. catalyzed lithiation under Barbier-type conditions at –78ºC and trapped with electrophiles (Scheme 4) [13]. However, Cyclic a -alkoxy-b-aminoalkyllithium compounds 17 and attempts to carry out the stepwise lithiation failed or gave 18 were prepared from the corresponding stannanes 15 and very low yields. After reduction with DIBALH or hydrolysis 16, respectively, at –78ºC (Scheme 3). The stability of these with LiOH, the corresponding diols can be obtained. organolithium compounds bearing a b-leaving group can be predicted by using the principle of microscopic reversibility In the case of a -hydroxyalkyltrimethylstannanes, the tin- along with Baldwin’s rules, since their b-elimination lithium transmetallation occurred when a carbamate is used decomposition is the reverse of n-endo-trig cyclization. The as protecting group [14]. Surprisingly MOM-protected stability of intermediates 17 decreased with increasing ring derivatives did not suffer transmetallation as in the case of a - size (up to n = 3). Oxazolidines 16 afforded after hydroxyalkylstannanes [15]. Best results were obtained using transmetallation and reaction with different electrophiles s-BuLi at –95ºC to give intermediates 24, which reacted with Functionalized Organolithium Compounds: New Synthetic Adventures Current Organic Chemistry, 2003, Vol. 7, No. 9 869 2 Scheme 5. Reagents: i, s-BuLi, THF, –95ºC; ii, R CHO; iii, AlH3, THF, rt; iv, H2O * Scheme 7. Reagents: i, s-BuLi, PhMe/Et2O, –78ºC; ii, Me2R SnBr; Scheme 6. Reagents: i, s-BuLi, TMEDA, Et2O, –78ºC, E = iii, MeOD; iv, BuLi, TMEDA, hexane, –78ºC. 1 Me3SiCl, Me3SnCl, R I. diols, which are the core unit of anti-HIV-1 protease agents by addition to a -aminoaldehydes or by dimerization with CuCl [19]. (S)-N-Benzylprolinol and rac-N-benzylpiperidine-2- methanol derived carbamates 30 were diastereoselectively lithiated in the presence of TMEDA or (–)-sparteine. An efficient kinetic resolution was observed by means of s-BuLi and (–)-sparteine in the case of 30 (n = 2) by abstraction of the pro-S hydrogen and further reaction with electrophiles. Enantioenriched (–)-(S)-30 (n = 2) remains unchanged under the same conditions [20]. The stability of anions derived from all of these b-aminoalcohol carbamates is not related to the cyclic intermediates 17 and 18 [12] and may arise from their dipole-stabilized nature [21]. aldehydes with good yields (Scheme 5). These adducts could The allylic carbanion derived from (E)-cinnamyl alcohol be transformed into diols by AlH3 reduction at room carbamates 31 is configurationally unstable and equilibrates temperature [14]. at temperatures below –50ºC. Carboxylation, acylation with acyl chlorides, stannylation, and silylation took place at the Direct deprotonation of carbamates derived from b- a -position with stereoinversion (79-86% ee) in the presence aminoalcohols 27 by means of s-BuLi in the presence of of (–)-sparteine [22a]. Related allylic anion derived from 9- TMEDA in ether at –78ºC afforded, after trapping with chloro-5-aza-2,7-nonadienol carbamate was used in the electrophiles, anti/syn mixtures of products 28 in ca. 3:1 asymmetric synthesis of 3,4-divinylpyrrolidine [22b]. ratio (Scheme 6) [16]. Deprotection with trifluoroacetic acid yielded the corresponding chain elongated b-aminoalcohols. Benzyllithium compounds bearing an oxygenated Related 2-aminoalkyl carbamates 29 can be substituent at the a -position were prepared by deprotonation diastereoselectivity deprotonated in the presence of (–)- and were configurationally stable. However, depending on sparteine [17] at the pro-S-hydrogen, and with low selectivity the electrophile, inversion (RHal, MeOCOCl, CO2, CS2, in the case of TMEDA [18]. The lithio derivatives of RCN, RCOCl, PriNCO) or retention [MeOH, AcOH, carbamates 29 were used in the synthesis of 1,4-diamino-2,3- (MeO)2CO, esters, anhydrides] was observed [23]. 870 Current Organic Chemistry, 2003, Vol. 7, No. 9 Najera and Yus Scheme 10. Reagents: i, t-BuLi,