1,4-addition cuprate

A number of alternative multi-step procedures for the synthesis of a-tert-alkyl ketones are known, none of which possess wide generality. A previous synthesis of 2-tert-penty1cyclopentanone involved reaction of N-1-cyclopentenylpyrrol 1 dine with 3-chloro-3-methy1-l-butyne and reduction of the resulting acetylene (overall yield 46 ). However, all other enamines tested afford much lower yields. Cuprate addition to unsaturated ketones may be useful in certain cases. Other indirect methods have been briefly reviewed. ... 

Stereoselective addition of cuprates to ji-alkoxy enoates of type 49 [17] isee Sdiemes 6.8 and 6.9) bas been used in die crrnstruction of polypropionate-type structures. Tlius, a sequence of diastereoselective cuprate addition, etiolate for-ruabon, and diastereoselective oxygenation widi Davis s reagent bas been applied iteratively to provide a Cio segment of Rifaruycin S i60) [ 17c, d]. 

Scli ir 6.9. Conctriictlon of the polypropionate cegment of Rlfamycln S through IteraHve dlactereocelectlve cuprate addition to ao/clic enoatec. a) Me Cn Li, TMSCI,... 

Sdieine 6.12. Diactereocelective cuprate addition to 2 enone 61 - Ice/ ctep towardc the cynthecic of ico[7]-levnglandin D . TBS = t-biityidimethylcilyl)... 

Sdieire 6.20. Diactereocelective cuprate addition to cteroidal enone 95 (MOM = methoKymethyl). 

Tab. 6.3. Reciiltc of diactereocelectii/e cuprate addition to d-fiinctionalized enoatec 102-107 (TBS = t-bcityldimethylcih/l, Bn = benzyl).

In addition to the boron trifluoride-diethyl ether complex, chlorotrimcthylsilanc also shows a rate accelerating effect on cuprate addition reactions this effect emerges only if tetrahydrofuran is used as the reaction solvent. No significant difference in rate and diastereoselectivity is observed in diethyl ether as reaction solvent when addition of the cuprate, prepared from butyllithium and copper(I) bromide-dimethylsulfide complex, is performed in the presence or absence of chlorotrimethylsilane17. If, however, the reaction is performed in tetrahydrofuran, the reaction rate is accelerated in the presence of chlorotrimethylsilane and the diastereofacial selectivity increases to a ratio of 88 12 17. In contrast to the reaction in diethyl ether, the O-silylated product is predominantly formed in tetrahydrofuran. The alcohol product is only formed to a low extent and showed a diastereomeric ratio of 55 45, which is similar to the result obtained in the absence of chlorotrimethylsilane. This discrepancy indicates that the selective pathway leading to the O-silylated product is totally different and several times faster than the unselective pathway" which leads to the unsilylated alcohol adduct. A slight further increase in the Cram selectivity was achieved when 18-crown-6 was used in order to increase the steric bulk of the reagent. 

There are numerous examples of cuprate additions to 4-alkoxy-2-cyclopentenones, which proceed with excellent tram diastereoselection16. 

This 1,2-asymmetric induction has been attributed to stcric and stcrcoclectronic factors. Similarly, the cuprate additions to 4-alkylcyclopentenones l7 -19, and 4-alkylcyclohexcnones16 b-18 proceeded with very high trans diastereoselection. The copper iodide catalyzed addition of propylmagnesium bromide to 4-methyl-2-cyclohexenone gave a trans/cis ratio of 80 20, whereas the addition to 5-methyl-2-cyclohexenone produced a transjcis ratio of 93 72 3-Silyloxy system 3 gave the trans-adduct 4 on treatment with butylcopper-boron trifluoride reagent20. 

The stereochemistry at C(4) and C(6) was then established. The cuprate addition in Step C occurred anti to the substituent at C(2) of the pyran ring. After a Wittig... 

Kant and coworkers [89] synthesized cefzil (2-167) through a Normant cuprate addition to allene 2-164, readily available from inexpensive penicillins, to give 2-165, which cyclized to the cefzil precursor 2-166 in a SN -type reaction (Scheme 2.38). The conversion of 2-166 into 2-167 was already known [90]. 

An alternative method to prepare (Mormyl esters uses different building blocks to assemble the 1,4-dicarbonyl system and is complementary in many cases.10 Base-catalyzed addition of nitromefhane to a, J-unsaturated esters, followed by a variation of the Nef reaction, provides y-dialkoxy-substituted esters. The scope of this sequence has not yet been explored. Another approach involves cuprate additions to norephedrine-derived 2-alkenyloxazolidines this process allows small-scale synthesis of several p-formyl esters in optically active form (ee up to 95%).11... 

Scheme 2.22 Synthesis of/ -allenic esters 65 by 1,6-cuprate addition to 2-en-4-ynoates 64 and regioselective enolate protonation.

Scheme 2.23 1,6-Cuprate addition to different acceptor-substituted enynes 66.

Remarkably, the regioselectivity of the cuprate addition to acceptor-substituted enynes is also insensitive to the steric properties of the substrate. Thus, enynes with tert-butyl substituents at the triple bond (e.g. 68) underwent 1,6-additions even when the cuprate was also sterically demanding (Scheme 2.24) [47]. The method is therefore highly suitable for the preparation of sterically encumbered allenes of type 69. 

Scheme 2.24 Synthesis of sterically encumbered allenes by 1,6-cuprate addition.

Scheme 2.27 Regioselectivity of the protonation of the allenyl enolate obtained by 1,6-cuprate addition to enynoate 74.

Scheme 2.28 Functionalized allenes obtained by 1,6-cuprate addition to acceptor-substituted enynes and regioselective enolate trapping with methyl triflate (77), aldehydes (78, 79), ketones (80) and silyl halides (81).

Scheme 2.29 Diastereoselective 1,6-cuprate addition to chiral 5-alkynylidene-l, 3-dioxan-4-one 82.

Scheme 2.33 Synthesis of highly unsaturated allenes byl,10-and 1,12-cuprate addition.

Scheme 18.42 Synthesis of enprostil (115) by consecutive cuprate additions [124] (MOM = methoxymethyl PPTS = pyridinium p-tuolenesulfonate 2-Th = 2-thienyl).

Scheme 18.48 Synthesis of the allenic amino acid derivative 151 by 1,6-cuprate addition [15b] (Boc = tert-butoxycarbonyl).

Similarly, the benzannulated enyne-allenes 172 and 173 were prepared from the propargylic acetates 171 by cuprate addition or by Pd-catalyzed addition of arylzinc chloride (Scheme 20.35) [49]. The presence of a butyl group and a p-anisyl group at the allenic terminus of 173a and 173b permits competition between a formal ene reaction and a formal Diels-Alder reaction leading to 174 and 175, respectively. 

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