Copper-Mediated Addition and Substitution Reactions of Extended Multiple Bond Systems Norbert Krause and Anja Hoﬀmann-Ro¨Der

Modern Organocopper Chemistry. Edited by Norbert Krause Copyright > 2002 Wiley-VCH Verlag GmbH ISBNs: 3-527-29773-1 (Hardcover); 3-527-60008-6 (Electronic) 145 4 Copper-mediated Addition and Substitution Reactions of Extended Multiple Bond Systems Norbert Krause and Anja Hoffmann-Ro¨der 4.1 Introduction Since the pioneering work of Gilman et al., who carried out the first investigations into organocopper compounds RCu [1] and lithium diorganocuprates R2CuLi [2], the latter reagents (still referred to even today as Gilman reagents) have been be- coming widespread among organometallic reagents used for carbon-carbon bond formation. In particular, the seminal work of House et al. and Corey et al. has served to establish organocuprates as the reagents of choice not only for substitution reactions of many saturated (haloalkanes, acid chlorides, oxiranes) and unsaturated (allylic and propargylic derivatives) electrophiles, but also for 1,4-addition reactions to a; b-unsaturated carbonyl compounds and, last but not least, for car- bocuprations of non-activated alkynes [3]. In these processes, the unique reactivity of organocuprates relies on the interplay of the ‘‘soft’’, nucleophilic copper and the ‘‘hard’’, electrophilic lithium ion, offering control over reactivity and selectivity through ‘‘fine-tuning’’ of the reagent. Most of the tremendous achievements in various fields of organocopper chemistry over the last few decades are highlighted in this book. These include the elucidation of the structures of organocopper compounds [4] and the mechanism of their transformations [5] (Chapts. 1 and 10), new copper-mediated and copper-catalyzed processes [6] (Chapts. 2, 3, and 5), diastereoselective reactions (Chapt. 6), and highly enantioselective substitution and conjugate addition reactions [7] (Chapts. 7 and 8). The high standards attained in these fields are documented in numerous applications of copper-promoted transformations in total synthesis (Chapt. 9). As far as substrates are concerned, while the usual 1,4-addition and 1,3-substi- 0 tution (SN2 ) reactions of simple unsaturated substrates have so far predominated, analogous transformations of ambident substrates with extended multiple bond systems (i.e., with two or more reactive positions) have come to attention only re- cently. Here, systematic investigations have shown that such 1,5-substitutions and even 1,6- and 1,8-addition reactions proceed highly regioselectively and ste- reoselectively, in particular when the substrate contains at least one triple bond besides one or more conjugated double bonds. These unusual reaction types not 146 4 Copper-mediated Addition and Substitution Reactions of Extended Multiple Bond Systems only open up novel routes to interesting target molecules, but also provide deeper insights into the mechanism of copper-mediated carbon-carbon bond formation [3o, 8]. 4.2 Copper-mediated Addition Reactions to Extended Michael Acceptors 4.2.1 Acceptor-substituted Dienes Thanks to their ambident character, acceptor-substituted dienes can provide several isomeric products in copper-mediated Michael additions, therefore making it particular important to control not only the regioselectivity but also the stereose- lectivity of these transformations (Scheme 4.1). Scheme 4.1. Regioselectivity in conjugate addition reactions to acceptor-substituted dienes. Besides direct nucleophilic attack onto the acceptor group, an activated diene may also undergo 1,4- or 1,6-addition; in the latter case, capture of the ambident enolate with a soft electrophile can take place at two different positions. Hence, the nucleophilic addition can result in the formation of three regioisomeric alkenes, which may in addition be formed as E=Z isomers. Moreover, depending on the nature of nucleophile and electrophile, the addition products may contain one or two stereogenic centers, and, as a further complication, basic conditions may give rise to the isomerization of the initially formed b,g-unsaturated carbonyl compounds (and other acceptor-substituted alkenes of this type) to the thermodynami- cally more stable conjugated isomer (Eq. 4.1). 4.2 Copper-mediated Addition Reactions to Extended Michael Acceptors 147 ð4:1Þ The first example of a cuprate addition to an acceptor-substituted diene was reported by Na¨f et al. [9], who used lithium di-(Z)-1-heptenylcuprate in a Michael addition to dienoate 1 (Eq. 4.2). The reaction proceeded highly regioselectively, furnishing a 1:1 mixture of the two isomeric 1,6-adducts 2, which were converted into the Bartlett pear constituent ethyl (2E,6Z)-2,6-dodecadienoate (3) by basic isomerization. ð4:2Þ In analogous reactions, several other groups reported the exclusive formation of 1,6-addition products, suggesting that not even the choice of the organocopper reagent affected the regioselectivity of the transformation [10]. Whereas the use of monoorganocopper compounds predominantly resulted in the formation of adducts with E configurations, the corresponding Gilman cuprates R2CuLi yielded only 1:1 mixtures of the E and Z isomers [10b]. Ultimately, Yamamoto et al. [3f, 11] were able to show in their seminal contributions that even 1,4-additions of organocopper reagents to activated dienes are feasible: while the reaction between methyl sorbate (4) and the reagent formed from n-butylcopper and boron trifluoride mainly gave the 1,4-adduct 5, the corresponding Gilman cuprate nBu2CuLi again exclusively provided the 1,6-addition product 6 (Eq. 4.3). The organocopper compounds RCuÁBF3 are synthetically very useful (in natural product synthesis, for example; cf. Chapt. 9) and so have become commonly referred to as Yamamoto reagents [3f ]. ð4:3Þ Michael additions of organocopper reagents to acceptor-substituted dienes have found widespread application in target-oriented stereoselective synthesis [12]. For 148 4 Copper-mediated Addition and Substitution Reactions of Extended Multiple Bond Systems example, the chiral cuprate 8, containing a Scho¨llkopf bislactim ether moiety, was used in the first total synthesis of the antimycotic dipeptide chlorotetaine (10; Eq. 4.4) [12d]. Although the nucleophilic addition to dienone 7 in this case did not proceed regioselectively, furnishing only a 63:37 mixture of the 1,6- and 1,4-adducts, the former compound was successfully converted over several steps into diastereo- merically and enantiomerically pure chlorotetaine (10). ð4:4Þ While copper-catalyzed Michael additions to acceptor-substituted dienes using Grignard reagents as nucleophiles were reported even earlier than the corresponding additions of (stoichiometric) organocuprates, the former transformations have largely been restricted to the synthesis of steroid hormones. In this context, in addition to tetrahydro-3H-naphthalen-2-ones, which were used as model substrates for doubly unsaturated steroids [13, 14], estradiol derivatives bearing an alkyl chain in the 7a-position are especially interesting target molecules, due to their high af- finity for and specificity towards estrogen receptors [15, 16]. These unsaturated steroids may thus be particularly useful for the treatment of mammary tumors (breast cancer) [15]. As regards preparative aspects, however, the nucleophilic 1,6- addition to doubly unsaturated D4;6-steroids should proceed not only with the de- sired regioselectivity [13, 14, 15b, 16], but also in a diastereoselective manner, since only the 7a isomers are effective enzyme inhibitors [15b]. Although the diastereoselectivity of the copper-catalyzed 1,6-addition of methyl Grignard reagents to D4;6-steroids may be dependent on the substitution pattern of the substrate [13a], general preference for attack from the a side has frequently been observed [13]. Wieland and Auner [13e], for example, reported an a selectivity of 90% in the copper-catalyzed 1,6-addition of MeMgBr to dienone 11 (Eq. 4.5). The product 12 was converted over several steps into 7a-methylestrone (13), a precursor of several highly active steroidal hormones. 4.2 Copper-mediated Addition Reactions to Extended Michael Acceptors 149 ð4:5Þ In contrast to this, the introduction of longer alkyl chains with the aid of copper- promoted 1,6-addition reactions to D4;6-steroids normally proceeds with unsatis- factory a:b ratios [15b, 16]. In some cases, improvement of the diastereoselectivity by ‘‘fine tuning’’ of the reaction conditions has been possible. The ratio of the epimeric products 15 and 16 in the copper-catalyzed 1,6-addition of 4-pentenylmagnesium bromide to dienone 14, for example, was improved from 58:42 to 82:18 by adjust- ments to the quantity of nucleophile and the solvent composition (Eq. 4.6) [16f ]. ð4:6Þ 150 4 Copper-mediated Addition and Substitution Reactions of Extended Multiple Bond Systems Aberrant behavior, however, has been observed when using bicyclic tetrahydro-3H- naphthalen-2-ones as Michael acceptors: the 1,6-addition of cyano-Gilman cuprates or Grignard reagents (catalyzed by copper arene thiolate 18) proceeds with high trans selectivity, irrespective of the transferred group (Eq. 4.7) [17]. NMR spectro- scopic investigations have found that formation of p-complexes at the double bond adjacent to the carbonyl group, similar to those observed in 1,6-cuprate additions to acceptor-substituted enynes (Sect. 4.2.3), are involved in these transformations. Nevertheless, deeper insight into mechanistic features, which should be highly re- warding for preparative applications, is still awaited. ð4:7Þ 4.2.2 Acceptor-substituted Enynes As for conjugate addition

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