REVIEW Lithium Enolates: Capricious Structures – Reliable ...szolcsanyi/education/files/Organicka%20chemia... · REVIEW Lithium Enolates: Capricious Structures – Reliable Reagents

REVIEW

Lithium Enolates: �Capricious� Structures – Reliable Reagents for Synthesis

by Manfred Braun

Institut f�r Organische und Makromolekulare Chemie, Universit�t D�sseldorf, Universit�tsstrasse 1,DE-40225 D�sseldorf

(phone: þ 492118114731; fax þ 492118115079; e-mail: [email protected])

The first part of this review article deals with the structures of enolates. The development of researchin this field during the last half century will be illustrated by highlightening seminal contributions, while,by no means, an attempt of comprehensiveness is made: the choice of spotlights has, admittedly, apersonal touch. Aside from derivatization of lithium enolates and their crystal structures that meanwhileare classics, more recent solution studies are presented. In the second part, it will be shown bycontributions of our laboratory that, despite their complicated structures, lithium enolates are reliable�workhorses� in synthesis with emphasis being given to stereoselective C�C bond forming reactions dueto the Pd-catalyzed allylic alkylation of non-stabilized, preformed enolates.

Introduction. – This tour d�horizon on lithium enolates, written under a personalretrospective, is based on a lecture presented by the author on the occasion of therenewal of the doctorate degree to Professor Dieter Seebach at Karlsruhe Institute ofTechnology (KIT). Indeed, Dieter Seebach had graduated in 1964 as a doctoratestudent of Professor Rudolf Criegee at the Technische Hochschule Karlsruhe at thattime, and the 50th anniversary of this event was celebrated by the Faculty of Chemistryand Biosciences at KIT and the Chemische Gesellschaft Karlsruhe on July 8, 2014.The chemistry of lithium enolates is one of the research interests the author shareswith Professor Seebach, albeit focussing on and contributing to different topics in thefield.

The �Capricious� Lithium Enolates: Early Investigations, Crystal Structures andSolution Studies. – When the author was taught elementary organic chemistry as astudent at the TH Karlsruhe, enolate chemistry looked simple, as illustrated by theequation (Fig. 1) taken from the1965 edition of the textbook �Basic Principles ofOrganic Chemistry� of J. D. Roberts and M. C. Caserio [1]. It was the first of its kind thatwas based on reaction mechanisms, and it became the author�s favored textbook andhelped him substantially in understanding organic chemistry, whereas other contem-porary textbooks on elementary organic chemistry confronted the students with atremendous and confusing number of compounds and a plethora of trivial names – adidactic concept that was rather terrifying than stimulating.

The author owes the fact that he became attracted to organic chemistry also toanother experience during his study: in the fall semester of 1968, the young �Habilitand�

Helvetica Chimica Acta – Vol. 98 (2015) 1

� 2015 Verlag Helvetica Chimica Acta AG, Z�rich

Dr. Dieter Seebach gave a very intensive five-weeks seminar (four hours per day, fivedays per week, with a written exam every Saturday) on fundamental organic chemistry,compulsory for us, before we were allowed to enter the laboratory course. In Fig. 2, aphoto taken during this course with �Saalassistent� Dr. Dieter Seebach, is presented.Many of my colleagues became fascinated by organic chemistry due to this course, andsome of us (Volker Ehrig, Karl-Heinz Geiss, and the author) became later members ofthe Seebach group that, in those days, consisted essentially of the �Chef �, Albert Beck,and Hermann Daum, the first doctoral student.

Helvetica Chimica Acta – Vol. 98 (2015)2

Fig. 1. �Formation of the enolate anion by removal of an a-hydrogen by base is the first step in the aldoladdition� [1] (copied from [1])

Fig. 2. In the organic laboratory course at TH Karlsruhe in 1968 with Dr. Dieter Seebach (left)

The equation of enolate formation shown in Fig. 1 does not foreshadow any�caprice� of enolate structures. On the contrary, it simply describes an enolate as anambident anion that can be represented by two resonance formulae, the oxyanionic andthe carbanionic one.

The simple view on enolate structures represented by Fig. 1 was correct,satisfactory, and adequate, as long as reactions with enolates were run in highly polar,aqueous, or at least protic media, because, in this milieu, dissociation occurs at least to acertain extent. Therefore, the cation can be widely ignored, as it becomes evident fromFig. 1 and was general practice at the time. However, the situation changedfundamentally, when enolate chemistry switched from the aqueous phase to aproticmedia such as various cyclic and acyclic ethers, chlorinated hydrocarbons, arenes, oreven alkanes, frequently with tertiary amines as co-solvents: now the idea of any �free�,dissociated enolate anion became obsolete. This development in the chemistry of�preformed enolates�1) was marked by the beginning of the �LDA era� [3] and initiatedby Wittig�s seminal concept of the �directed aldol reaction� [4]. Indeed, the non-nucleophilic strong base lithium diisopropylamide, �LDA� (1; Fig. 3) became the keyreagent and a standard base for the formation of preformed enolates. The generation ofLDA and its use for ester condensations were first described in 1950 by Levine andHamell who refer in their publication entitled �Condensations effected by the alkaliamides. IV. The reactions of esters with lithium amide and certain substituted lithiumamides� to the master thesis of Matthew Hamell that was submitted two years earlier[5a]. Thus, the �year of naissance� of LDA may be dated to 19482). Nevertheless, LDAbecame popular only after it had been used by Wittig and co-workers andrecommended in a review of 1968: �[. . .] lithium diisopropylamide proved to be aparticularly suitable metalating agent [. . .]� [4].

Soon, other dialkylamides [6] joined the collection of reagents for quantitative,irreversible a-deprotonation of carbonyl compounds to form lithium enolates: lithiumN-isopropylcyclohexylamide [7] (LICA; 2)3), lithium tetramethylpiperidide [8](LTMP, 3)4) and lithium hexamethyldisilazanide [9] (LiHMDS; 4)5) (Fig. 3). Notunexpectedly, LDA is not monomeric but forms aggregates, as clearly shown by thecrystal structure of the bis-solvated LDA dimer in THF, as disclosed in the fundamentalcontribution of Williard and Salvino (Fig. 4) [10].

We learned – mainly due to the seminal studies of House and co-workers – thatLDA and the related bases are the reagents of choice for an irreversible formation oflithium enolates under kinetic control, meaning that, in carbonyl compounds with


1) The topic was treated in – for that time – comprehensive and highly informative reviews [2a – 2d].Heathcock�s overview [2c] also included the historical development of the term�. For a more recentreview, see [2e], and for treatment of enolate chemistry in recent textbooks, see [2f].

2) At the same time, diisopropylaminomagnesium bromide was described by Frostick Jr. and Hauser[5b].

3) LICA provided the first general method for the preparation of stable solutions of ester enolates [7].4) LTMP was first used for the metallation of B-methyl-9-borabicyclo[3.3.1]nonane [8a] and shortly

later applied for ester condensations [8b]. For a crystal structure of LTMP, see [8c].5) For a review on hexamethyldisilazanides of alkali metals, see [9a]. The crystal structure of LiHMDS

was one of the first of the non-nucleophilic lithium amides [9b]. For a crystal structure of the diethyletherate, see [8c].

differing degree of substitution in a- and a’-positions, the less substituted, thermo-dynamically disfavored regioisomer forms predominantly or even exclusively – aphenomenon that considerably enhanced the versatility of preformed lithiumenolates6) [2a] [11] [12]. Seebach, Ehrig, and Teschner took advantage of thatregioselective deprotonation and used it in one of the very first asymmetric aldolreactions via lithium enolates [13]. As illustrated in Scheme 1, a H-atom is abstractedfrom Me(1) group upon treatment of (S)-3-methylpentan-2-one (5) with LDA,whereas the H-atom in a�-position, i.e., at the stereogenic center remains untouched.Subsequent addition to propanal leads to the formation of the aldol adduct 6. Fortoday�s standards, the diastereoselectivity (dr¼ 57.5 :42.5) appears rather moderate;nevertheless, this work deserves to be mentioned, because it served to establish theprinciple. According to the general practice in the Seebach group, the configuration ofthe stereogenic center (created in the aldol addition) was assigned by a classic


Fig. 3. Standard lithium amide bases for formation of lithium enolates

Fig. 4. Structure of bis-solvated dimer [LDA · THF]2 (copied [10])

Scheme 1. Diastereoselective Aldol Addition of (S)-5 through the Lithium Enolate

6) The rate for kinetic deprotonation can be enhanced substantially by the addition of Et3N in toluene(see [12c] [12d]).

transformation: Baeyer�Villiger (BV) oxidation, followed by esterification to product 7unambiguously revealed its (R)-configuration by comparison of the optical rotationwith that reported in the literature. This work dates back to the Giessen period of theSeebach group, a time the photo in Fig. 5 was taken, showing Professor Seebach andAlbert Beck during a barbecue party in the forests near Giessen.

When, as outlined above, we will have to take into account the metal in thechemistry of preformed enolates, the question of the mode of binding obviously arises,meaning whether the metal is linked to the carbonyl O-atom (O-bound enolates 8) orto the a-C-atom (C-bound enolates 9). In addition, a third structure is possible, whereinthe metal forms a h3-bond to the enolate (oxallyl enolate 10) (Fig. 6)7).


Fig. 5. Professor Dieter Seebach and Albert Beck in the Giessen years

Fig. 6. General modes of binding in enolates (X¼ alkyl, aryl, H, OR, NR2)

If an enolate adopts the O-bound structure, there is an obvious stereochemicalconsequence in case that the a-position is carrying non-identical substituents: due tothe C¼C bond character, enolates may form as cis- or trans-diastereoisomers8) and thequestion arises whether they do interconvert under the conditions they are generatedand undergo reactions.

Chronologically, one of the first studies that addressed the configurational stabilityof ketone enolates was performed by House and Trost who generated [25] trans- andcis-enolates 12 and 14 from enol acetates 11 and 13, respectively, with MeLi. The


7) According to today�s knowledge, there is clear evidence indicating that enolates of groups 1, 2, and13 metals occur as the O-bound tautomers 8; the same holds in general for Si, Sn, Ti and Zr enolates[2] [3]. In this context, the seminal contributions of Kçster and Fenzl on the preparation of boronenolates and their spectroscopic characterization deserve to be mentioned [14a] [14b], but also thefirst crystal structure of a boron enolate disclosed by Williard and co-workers [14c]. The C-boundmetalla tautomers 9 are typical for the less electropositive metals [2d]. They have been postulatedoccasionally for Zn, in particular, in the context of the Reformatsky reaction [15], and Cu in thecontext of cuprate additions to enones [16]. C�Bound enolates of Mo, W, Mn, Re, Fe, Rh, Ni, Ir,and Pd have been detected and characterized [17], but one has to consider that they exist inequilibrium with the O-bound metalla tautomers. For a Pd enolate, for example, the activationbarrier for the interconversion of the two metalla tautomers has been determined to amount to ca.10 kcal · mol�1 [18]. The dynamic of O- and C-bound tautomers 8 and 9, respectively, with latetransition metals is obviously a delicate balance depending on the individual enolate, the metal, andthe ligands [19]. The third species, the oxallyl enolate 10 featuring a h3-metal bond, is also typical fortransition metals and may coexists with the O- and C-bound species in equilibria. Enolates withoxallyl structure 10 were obtained by directed preparation and characterized [20], and alsopostulated as reactive intermediates [21]. In recent years, enantioselective catalysis withintermediate Pd and Rh enolates became highly important [22].

8) In this article, the terms cis and trans are used to describe the configuration of enolates in general,whereby �cis� means that the OM substituent is on the same side as the higher priority group at thea-C-atom, and �trans� means that the OM substituent is on the opposite side. At a glance, thedescriptors (Z) and (E) might seem to be appropriate for O-metal bound enolates 8. However,application of the (E/Z) descriptors to ester enolates leads to the dilemma that enolateswith different metals but otherwise identical structures will be classified by opposite descrip-tors, as illustrated by Li and Mg enolates, respectively: the former would have to be termed (Z),the latter (E):

To circumvent this dilemma, it has been proposed that irrespective of the formalCahn�Ingold�Prelog criteria, the O-atom bearing the metal (the OM residue) is given a higherpriority, and the ipso-substituent X (in enolates 8) the lower one [2b]. This led, however, toconsiderable confusion in the literature where, for example, identical structures of ester or thioesterenolates were termed (E) by one and (Z) by another author; cf. [2b] and [23a] vs. [23b] and [23c].There is also a principal reason not to use this definition: the �hard� descriptors (E) and (Z) must notbe redefined. The �soft� descriptors cis and trans, however, can be used without violation of the strictdefinitions of the unequivocal (E) and (Z). This is also recommended in the textbook of Eliel andco-authors [24].

treatment of enol acetates of ketones with 2 equiv. of MeLi was known as a method forgenerating ketone enolates under concomitant formation of tert-butoxide. In a first SN2t

step, the ester is cleaved, and then the acetone liberated thereby is �destroyed� by the2nd equiv. of MeLi [2a]. The experiment of House and Trost revealed that lithiumenolates 12 and 14 do not isomerize even when kept at 738 for 40 min in 1,2-dimethoxyethane (Scheme 2), thus indicating the O-bound character of lithiumenolates. This was confirmed a few years later by direct NMR studies of the lithiumenolates of isobutyrophenone and AcOtBu, performed by Jackman and Haddon [26],and Rathke and Sullivan [27], respectively.

Profound insight into the structure and reactivity of lithium enolates came from theseminal contributions of Ireland et al. [28]. The evidence provided by their studies isbriefly summarized in Scheme 3. Based on a series of experiments, it was postulatedthat propanoates will form trans-enolates upon deprotonation with LDA in THF,whereas cis-enolates were assumed to arise when a strongly coordinating solvent likeHMPA (hexamethylphosphoric triamide) was used. The explanation for that becameknown as the �Ireland model� [2b] [2c] [29]. However, the diastereoisomeric lithiumenolates involved here were not characterized at the time, but their structures wereassigned indirectly based upon the following reactions: (E)-but-2-enyl propanoate 15was deprotonated under the different conditions, and the lithium enolates cis-16 andtrans-17 were transmetallated to the corresponding silicon enolates (silyl keteneacetals; i.e., Me3Si instead of Li in 16 and 17). These subsequently underwent a smooth[3,3]-sigmatropic rearrangement that became classic under the name Claisen�Irelandrearrangement [30]. It turned out that diastereoisomeric esters 18 and 19, respectively,were obtained from the different deprotonation conditions. The plausible assumptionwas that the transition state of the Claisen�Ireland rearrangement has a chair-likeconformation, and, therefrom, it was deduced that the lithium enolate, giving finally theester 18, must have adopted the cis-configuration of 16, the other one leading to theester 19 consequently trans-configuration 17. Thus, this assignment of configurations tothe lithium enolates is an indirect, albeit highly plausible one. The assumption thatenolate configuration does not change, and configurational integrity of lithium enolatesis retained under the conditions of transmetallation to the silicon enolates is highly


Scheme 2. Configurational Stability of Ketone Enolates cis-12 and trans-14

convincing in view of the profound work on the preparation and spectroscopiccharacterization of silicon enolates performed in the groups of House and Stork [2].

Had so long the structures of lithium enolates been deduced indirectly, asexemplified above, a direct insight came from a series a crystal-structure analysesperformed by Seebach and co-workers during the 1980ies, clearly evidencing the O-bound character of the enolate and determining the configuration of the resulting C¼Cbond [3] [31]. Fig. 7 highlights several of those structures that became �classics� inenolate chemistry: the tetrameric THF-solvated pinacolone enolate with a cubic Li4O4

core unit (Fig. 7,a)9) [32], the dimeric enolate of tert-butyl propanoate, co-crystallizedwith TMEDA (Fig. 7, b) [23b], and the dimeric enolate of N,N-dimethylpropanamidewith TriMEDA (Fig. 7,c) [35]. The structure of the ester enolate (Fig. 7, b) clearlyshows the trans-configuration and that of the amide enolate (Fig. 7,c) the cis-configuration at the C¼C bond. The length of these bonds (ca. 134 pm) is very similar tothose in enol ethers (132 pm) [23b]. A comprehensive overview on lithium enolatestructures known at the time is given in [3]. More recent studies revealed inter alia:dimeric and monomeric ketone-derived lithium enolates [36], as well as structures ofenolate aggregates with LDA [37], with chiral lithium amides [38] and with lithium


Scheme 3. Assignment of Enolate Configuration Based upon the Stereochemical Outcome of theClaisen�Ireland Rearrangement

9) Shortly later, the structure of the non-solvated hexameric structure of the lithium enolate ofpinacolone was disclosed by Williard and Carpenter [33]. Another early contribution to enolatecrystal structures came from van Koten and co-workers and revealed a tetrameric structure of thelithium enolate of 2-(dimethylamino)methylacetophenone [34].


Fig. 7. Selection of crystal structures of lithium enolates (copied from [3])

halides [39]. The latter are particularly interesting in view of the LiX effect [3], i.e., thesubstantial impact LiCl has on the reactivity and selectivity of lithium enolates.

The lessons, the chemist who intends to use enolate chemistry for asymmetricsyntheses, can learn from those crystal structures, are reliable and exact. Crystalstructures unambiguously answered the question of the O�metal or C�metal bindingfor those highly polar enolates and established enolate configurations. With respect totheoretical calculations, the parameters obtained from crystal structures serve asstarting points, but also as a control and corrigendum. As, however, organic reactionsare run in solution, the importance of studies on enolates and their aggregation insolution is self-evident.

It is beyond the scope of this short review to present even the most relevantcontributions that were made in the past decades in order to understand lithiumenolates in solution. Colligative measurements, including cryoscopy in THF at � 1088were conducted to find out the aggregation grade [40], but the modern NMRtechniques turned out as the most important tool for solution studies of enolates. Afterresearch in this field had been pioneered by Jackman and co-workers [41], seminalcontributions came mainly from Reich and co-workers [36] [42] [43], Collum and co-workers [44], and Williard and co-workers [45]. The questions to be answered by allthese studies were not only about the structure and solvation of the aggregates andmixed aggregates (with, for example, lithium amide bases used for deprotonation, theamine that results from deprotonation with theses bases, co-solvents, lithium salts,products such as lithium alkoxides in aldol additions) but, also quite importantly: isthere equilibration between all these aggregates? Which aggregate is responsible forstereoselectivity in reactions of the lithium enolates? If there are equilibria between theaggregates, are there parallel reactions with a certain substrate that may have differentreactivity and selectivity? Or is the equilibrium fast so that the relative amounts of theindividual components are irrelevant to the selectivity-determining and reactivity-determining steps? In other words: is there a Curtin�Hammett situation or not? Itseems that, in view of the �myriad structures of an enolate� (as stated by Paul Williard[46]), these answers can only be given for a certain combination of individual enolate,reactant, solvent, additive, temperature etc., and a general answer is simply notavailable.

The following studies on enolate reactions by spectroscopy in solution have beenchosen to exemplify contrary results, obtained with related lithium enolates, however,with different reactants. Streitwieser and co-workers [47] [48]10) used UV/VISspectroscopy to study the aggregation state of ion pairs in lithium enolates anddeduced from the concentration-dependent UV/VIS absorption of enolate chromo-phores that different aggregates of enolates can be identified based on their individualabsorption maxima. Due to its sensitivity, UV/VIS spectroscopy was considered asparticularly suitable to identify minor, but nonetheless highly reactive components inthe aggregation equilibria. Analysis of the absorption spectra of a mixture of aggregatesby the linear-algebraic �single value decomposition� method opens the possibility to�extract� the spectrum of the individual aggregate. The technique was applied to studythe reaction of the lithium enolate of 4-phenyl isobutyrophenone with alkyl halides


10) For an informative personal retrospective, see [48].

such as 4-(tert-butyl)benzyl bromide [47b]. The enolate 20 was shown to consist of amixture of monomeric and tetrameric contact ion pairs in THF. From the measuredequilibrium constant shown in Scheme 4, it is evident that the tetramer largelypredominates. Nevertheless, the kinetics determined for the reaction with 4-(tert-butyl)benzyl bromide provides direct evidence that the monomer of the lithium enolateis the reactive species in alkylation reactions even in the presence of a large excess oftetramer. Thus, a Curtin�Hammett situation applies for this particular reaction, but alsoin related cases, where tetramers, dimers, and mixed aggregates were present, butnonetheless, the monomer was identified as the reactive species.

However, one should be cautious with any generalization: in a recent study of Reichand co-workers [43], the aldol addition between the lithium enolate of 4-fluoroace-tophenone and 4-fluorobenzaldehyde in THF was followed by rapid-injection 1H-, 7Li-,and 13C-NMR spectroscopy. First, a metastable enolate dimer that dimerizes to a stabletetramer 21 was detected (Fig. 8). The reaction of 21 with the aldehyde was muchfaster than the desaggregation, so that a mechanism that involves predissociation priorto the aldol addition does not apply. Whereas an enolate/aldolate aggregate (3 :1) 22was identified as the first product of the reaction of the tetramer, the parallel reactionof the dimeric enolate leads to a 1 :1 enolate/aldolate aggregate as the primary aldolproduct. For reasons of simplification, only the course of the tetramer reaction isfollowed, as illustrated by Fig. 8. The mixed aggregate 22 was shown to react faster withthe additional aldehyde (k¼ 0.66 m

�1 s�1) than the homoaggregate 21 (k¼ 0.29 m�1 s�1)

of the enolate. The aldolate homo-oligomer 23 is formed as the final product. Theresults clearly revealed that there is not a single aldol addition of a single highly reactivespecies. Instead, there are several parallel aldol reactions, and each aggregate may haveits own reactivity and – if applied to asymmetric synthesis – its own stereoselectivity.These results support the intuitive mechanisms of the aldol reaction on a tetramer, assuggested by Seebach, Armstutz, and Dunitz, and the structure 24 they proposed mightwell represent the 3 : 1 enolate/aldolate aggregate [49]. The metastable dimer (notshown in Fig. 8) also undergoes an aldol addition, which is slightly (ca. 20 times) fasterthan that of the tetramer.


Scheme 4. Equilibrium between Monomeric and Tetrameric Enolate 20 and Predominant Reaction of theMonomer

Even the few, selected studies devoted to the structure and reactivity of enolatespresented here may justify to describe these species as �capricious�11). Even after half acentury of intense research in this field, the statement Hans Reich made recently still


Fig. 8. The aldol reaction of tetrameric lithium enolate 21 of 4-fluoroacetophenone with 4-fluorobenzal-dehyde in THF/Et2O 3 : 2 at � 1258 monitored by 19F rapid-injection NMR. The lines correspond tosimulations based on the kinetic scheme shown above with the rate constants indicated on the graph;

copied from [43], Supporting Information.

11) Computational studies, whose tools have improved substantially from semiempirical calculations inthe 1980ies and 1990ies, to actual and much more precise ab initio calculations and density-functional methods, have also been applied to obtain an insight into structure and reactivity oflithium enolates. Essentially, the computational studies confirm the experimental ones inunderlining the relevance of aggregates and mixed aggregates not only as the favored structuresof lithium enolates but also for their reactions, for example in alkylations and aldol additions. Forreviews, see [48] [50] [51], for more recent examples on calculations on lithium enolates, see [52].

seems to apply: �Clearly there is much we do not understand about lithium reagentaggregate reactivities� [43]. Synthetic chemists fortunately were not intimidated by theplethora of aggregates, solvates, and mixed solvates: they simply applied these reagentssuccessfully in synthesis, particularly asymmetric synthesis. Maybe the chemists�attitude: �just give it a try� is a key to success.

Lithium Enolates: Reliable Tools in Asymmetric Synthesis. – This will be topic ofthe second part of this article. The author, who is aware that a treatment, even a cursoryone, would require at least a monograph, focusses on the recent work of his group12)that is devoted to apply lithium enolate chemistry in Pd-catalyzed asymmetric allylicalkylations, the �Tsuji�Trost reaction�. The author encountered this reaction when hewas a doctorate student in Giessen and went to nearly located Marburg in order toattend a series of lectures given by the Visiting Professor Barry Trost in the early1970ies. In his legendary chalk-talks, he demonstrated to us, how Pd dramatically altersthe reaction of a nucleophile with allyl acetate, as displayed in Scheme 5 : fromsubstitution at the COO group to a substitution of the allyl moiety in the presence ofthe noble metal.

The Pd-catalyzed allylic substitution, discovered by Tsuji and thoroughly developedby the group of Trost, is outlined in its most simple asymmetric version in Scheme 6.Starting from a racemic allylic substrate 25, bearing identical residues R and a suitableleaving group such as acetate, carbonate, phosphate, halides, and others is treated witha Pd0 source to generate the palladium�allyl complex 26. The subsequent reaction witha nucleophile is directed by the chiral ligands L* at the noble metal so thatenantiomeric products 27 are formed in unequal amounts. In the last step, Pd0 is


12) Here, a short remark on doubly lithiated 2-hydroxy-1,2,2-triphenylethyl acetate (� HYTRA�) [53]might be justified – a contribution of our group to �lithium enolates as reliable reagents forsynthesis�. Indeed, it offered an early, practical solution for the acetate aldol addition [54], a longstanding problem in asymmetric synthesis.

The reader is referred to review articles [55] and applications of HYTRA in syntheses of naturalproducts and drugs [56], inter alia: g-amino-b-hydroxybutanoic acid (�GABOB�) [56a], theenantiomeric naphthoquinones shikonin and alkannin [56b], d- and l-digitoxose [56c], deoxy- andaminodeoxy furanosides [56d], a substrate for the enzyme 3-hydroxybutanoate dehydrogenase[56e], detoxinine [56f], tetrahydrolipstatin and related pancreatic lipase inhibitors [56g], statin [56h],statin analogs [56i], fluoroolefin peptide isoesters [56j], epothilone A [56k], the A-ring buildingblock of 1a,25-dihydroxyvitamin D3 [56l], building blocks of lankacidin C [56m], the C(1)�C(9)segment of bryostatin [56n], the C(20)�C(34) segment of the immunosuppressant FK-506 [56o],hypocholesterolemic pyranoyl steroids [56p], the a7 nicotinic receptor agonist AR-R17779 [56q],the immunoadjuvant QS-21Aapi [56r], a phenyl-laulimalide analog [56s], cyclopentane segments ofjatrophane diterpenes [56t], and macrocyclic precursors of lankacidins [56u]. In particular, HYTRAwas applied for the synthesis of enantiomerically pure HMG-CoA inhibitors [57], some of whosebecame best-selling drugs like atorvastatin [57a – 57d], fluvastatin [57e] [57f], and compactin [57g].

released and will enter the catalytic cycle again. This version of the allylic alkylationbecame known as the asymmetric allylic substitution and was thoroughly developed for�soft� nucleophiles13), i.e., in the case of carbon nucleophiles mainly for malonates andb-keto esters. Various research groups developed efficient chiral ligands L*, and thenumber of applications of their protocols is countless [59]. The method, however,suffered for a long time from its restriction to the �soft� nucleophiles, because �hard�nucleophiles, in particular the reactive enolates of alkali and alkaline earth metals, wereconsidered to be reagents that are unsuitable for this transformation found to beplagued by double allylation and moderate conversion [60]. Thus, it was stated that thereactions with �hard� nucleophiles �have been disappointing� [59d], and application ofZn, B, and Sn rather than the strongly basic lithium enolates was recommended for Pd-catalyzed allylic alkylations [61]. It seems that early, promising – although not yetenantioselective – protocols for the allylation of lithium enolates [62] were somehowforgotten for a while.


Scheme 5. Fundamental Difference in the Reaction of Allyl Acetate with a Nucleophile in the Presenceand Absence of Palladium, as Outlined in the Marburg Lectures by Professor Barry Trost

Scheme 6. General Course of the Asymmetric Pd-Catalyzed Allylic Alkylation

13) The terms �hard� and �soft� refer to their use in the relevant literature at the time. The author isaware of the problematic and obsolete character of this terminology and today�s much moreadequate approaches for a classification of nucleophilicity [58].

It is quite obvious that the use of prochiral preformed enolates would substantiallyenhance the versatility of such reactions because this would permit not only creation ofa stereogenic center in the allylic, but also in the homoallylic position. Indeed, Trost andSchroeder reported in 1999 [63a] the first enantioselective variant wherein the tinenolate 28 derived from 2-methyltetralone was reacted with allyl acetate. The use of theC2-symmetric ligand (S,S)-29 (�Trost�s ligand�) permitted them to obtain the allylatedketone 30 in 88% ee (Scheme 7)14) [63].

Shortly later, in 2000 we reported, the first diastereoselective and enantioselectivePd-catalyzed allylic alkylation [64]. For this purpose, the magnesium enolate 31a,generated from cyclohexanone, was reacted with diphenylallyl acetate 32a, and (R)-BINAP (33) served as the optimum chiral ligand. Thus, the alkene 34 was obtained as anearly pure diastereoisomer with 99% ee (Scheme 8). The relative configuration of 34was established by the crystal structure, also shown in Scheme 8. At first, it may appearsurprising to see that the bulky allyl residue is located in the axial position of the chairconformer. It is, however, not unprecedented that, in cyclohexanones, the stericallydemanding a-substituent is forced to occupy the axial position in order to avoid oxallylstrain [65]. The absolute configuration of 34 was assigned by chemical correlation asfollows: both carbonyl groups of the keto aldehyde, obtained by ozonolysis, wereconverted to dithiane moieties. Finally, treatment with Raney-Ni led to compound (�)-35, whose configuration was established as (S) by comparison with a sample previouslyprepared by Seebach and co-workers [66]. In [64], we reported the first diastereose-lective and enantioselective allylic alkylation of the lithium enolate of an acyclicketone. Later, this type of nucleophiles was intensively studied by Hou and co-workers[67]. Lithium enolates of amides and oxindoles were submitted to asymmetric allylic-alkylation protocols elaborated by Hou and co-workers [68], and Trost and Frederiksen[69], respectively. Finally, lithium enolates of a-alkoxy ketones were used by Evanset al. [70] as nucleophiles in enantioselective Rh-catalyzed allylations.

Diphenylallyl acetate 32a is a standard substrate for testing the performance of newligands according to the reaction outlined in Scheme 6, less suitable, however, forsynthetic purposes and applications. Therefore, we extended our protocol to


Scheme 7. Trost�s Enantioselective Allylic Alkylation of 2-Methyltetralone through Tin Enolate 28

14) It was mentioned that the reaction is also possible with the lithium enolate [63].

dimethylallyl carbonate 32b (Scheme 9) that was allowed to react with the lithiumenolates 31b again using (R)-BINAP (33) as the chiral ligand at Pd, while LiCl wasused as an additive. The alkene 36 was formed again with high diastereoselectivityand ee. Comparable results were obtained with the lithium enolate of cyclopentanone.The finding that the allylation product 36 was isolated in only relatively lowyield, accompanied by non-racemic allylic substrate 32b, indicates a kinetic resolution[71].

The protocol with a reduced catalyst loading was successfully applied to anenantioselective allylation of the lithium enolate 31b of cyclohexanone with allylcarbonate 32c, and (S)-2-allylcyclohexanone (38) thus became available in 94% ee byusing the chiral ligand (S)-Cl-MeO-BIPHEP 37. Here again, the presence of theadditive LiCl was beneficial to both reactivity and stereoselectivity (Scheme 9) [72].For a procedure in Organic Syntheses [73], the reaction was run on a larger scale, andthe allylation product 38 became available in 10-g quantities without loss in selectivityin 76% chemical yield. A subsequent racemization of the product with a stereogenic


Scheme 8. Diastereoselective and Enantioselective Allylic Alkylation of Cyclohexanone with Diphenyl-allyl Acetate (32a). Crystal structure of allylation adduct 34 and conversion into (�)-(S)-35 for

determination of the absolute configuration are shown.

center in the homoallylic position did not occur. Various approaches towards theTsuji�Trost reaction of preformed ketone enolates have been the topic of severalreview articles [74].

It deserves to be mentioned that simultaneously to our direct allylation approachvia lithium enolates, the research groups of Tunge, Stoltz, and Trost [75] elaboratedprotocols that became known as decarboxylative asymmetric allylic alkylations [76].These procedures are enantioselective versions of the preceding independentlyaccomplishments of Tsuji and Saegusa, and their co-workers [77], using either allylicesters of b-keto acids or allyl enol carbonates. Both undergo decarboxylations uponexposure to a Pd0 source, and the ion pair of allylpalladium cation and enolate anion arecombined in an enantioselective manner, when suitable chiral ligands are used. Themethod is particularly useful to obtain ketones with quaternary stereogenic centers inthe position to a-carbonyl. It was evidenced by Trost and co-workers that thestereochemical outcome in the decarboxylative asymmetric allylic alkylation isdifferent from that of the direct allylation of lithium enolates [78].

After it had been shown that preformed enolates are compatible with catalyticallygenerated allyl-Pd complexes, the question of the stereochemical course came up. Forthe attack of a C-nucleophile to a p-allyl-Pd complex 40, two pathways have to be takeninto account: the outer-sphere mechanism involves the approach of the nucleophilefrom the face opposite to that occupied by Pd. The inner-sphere mechanism postulatesa pre-coordination to Pd and the nucleophile leading to 42, followed by a bond-formingreaction by reductive elimination. As a consequence, the nucleophile approaches fromthe same face as the transition metal is located. Given that, in the precedent step, theleaving group of the allylic substrate 39 has been replaced by the transition metal underinversion, the outer-sphere mechanism leads to a net retention (!41), whereas theinner-sphere path results in net inversion (!ent-41) (Scheme 10). It was generally


Scheme 9. Diastereoselective and/or Enantioselective Allylic Alkylation of Lithium Enolate 31b

accepted that �soft� nucleophiles favor the outer-sphere mechanism, whereas �hard�nucleophiles follow the inner-sphere mechanism [59d], the border between �hard� and�soft� nucleophiles being drawn at a pKa value of ca. 25 [59d] or 20 [78] of thecorresponding acid. As ketones are CH acids with pKa values – according to theBordwell scale [79] – around that �border�, the stereochemical outcome was hardlypredictable. Therefore, we undertook an experimental study of the allylation of thelithium enolates of acetophenone and cyclohexanone.

The probes (Z)-43 and (E)-48, both enantiomerically and diastereoisomericallypure allylic substrates [80], which we had made accessible based on our earlier work onthe chemistry of chiral lithium carbenoids [81], were submitted to the standardallylation protocol, however, with the achiral ligand dppf (1,1’-bis(diphenylphosphi-no)ferrocene), as the stereocontrol was left to the substrate. The results are outlined inSchemes 11 and 12 for the lithium enolate of acetophenone with the additive LiCl. Thereaction of (Z)-configured allylic acetate 43 led to the formation of the ketone 47 as asingle diastereoisomer. Obviously, the new C�C bond had formed under overallinversion of the configuration, but the reaction was accompanied by an isomerization ofthe C¼C bond. This stereochemical outcome is rationalized by assuming a p�s�p

interconversion as follows: starting from (Z)-alkene 43, initially the p-allyl complex 44is formed by replacement of the AcO group under inversion. Spontaneously, the p-complex 44 undergoes a conversion through equilibration via the s-complex 45a and itsrotamer 45b into the p-complex 46. This is finally attacked by the enolate from the faceopposite to the Pd. Thus, the overall inversion observed in the formation of (E)-47results from two substitutions occurring each under inversion and a – thermodynami-cally driven – isomerization of the (Z)- into an (E)-C¼C bond through the p�s�p-mechanism (Scheme 11) [72].

The formation of the diastereoisomeric product 50 from the substrate (E)-48 isplausibly rationalized by a twofold inversion, in the formation of the p-complex 49 and,secondly by an approach of the nucleophilic enolate. A thermodynamically controlled(Z)- to (E)-interconversion does not occur here, and thus, a net retention in the allylicalkylation results (Scheme 12). Analogous stereochemical outcome was observed forthe reaction of the lithium enolate of cyclohexanone with the allylic substrates (Z)-43and (E)-48. The results, shown in Schemes 11 and 12, clearly establish the outer-sphere


Scheme 10. Stereochemical Course of the Pd-Catalyzed Allylic Substitution. Inner- and Outer-SphereMechanisms

mechanism for the Tsuji�Trost reaction of ketone lithium enolates [72]. Shortly afterour publication, the outer-sphere mechanism for lithium enolates as nucleophiles wasunambiguously confirmed by Trost et al. by using a different probe [78].


Scheme 11. Stereochemical Course of the Pd-Catalyzed Allylic Substitution at the Substrate (Z)-43 as aDiastereoisomerically and Enantiomerically Pure Probe

Scheme 12. Complementary Stereochemical Course of the Pd-Catalyzed Allylic Substitution at theSubstrate (E)-48 as Diastereoisomerically and Enantiomerically Pure Probe

After we had shown that stereoselective allylic alkylation reactions of ketoneenolates are indeed feasible, we turned next to lactone enolates – another class of �hard�nucleophiles15); although previous work on their use in Tsuji�Trost reactions had notbeen promising [84]. Fortunately, our protocol, experienced for the lithium enolates ofketones, was equally successful for the lactone enolates. Again, the additive LiClchloride was crucial, and, in its presence, the allylation was run at � 788. This isimportant in view of the thermal instability, the lithium enolates of carboxylic esters,and lactones encounter. Thus, d-valerolactone 51 was deprotonated with LDA, and thelithium enolate 52 generated in this way was submitted to a Pd-catalyzed reaction withallyl carbonate 32c or dimethylallyl carbonate 32b in the presence of LiCl (Scheme 13).Either (R)- or (S)-BINAP (33) were used as chiral ligands at the transition metal. Theallylation product 53 was obtained in 84.6% ee which appears remarkable in view of thefact that the single stereogenic center of this compound might easily undergo aracemization under the strongly basic reaction conditions. With the branched allylicsubstrate 32b, high diastereoselectivity was obtained in favor of the syn-configuredproducts 54. Depending on the enantiomer of the chiral catalyst, either 54 or ent-54


Scheme 13. Diastereoselective and/or Enantioselective Allylic Alkylation of d-Valerolactone 51 throughIts Lithium Enolate 52

15) Early attempts using ester enolates for Pd-catalyzed allylic alkylations encountered difficulties andwere disturbed by side reactions [82]. So far, the only successful applications are those of zincenolates derived from a-amino esters, as described by Kazmaier and co-workers. Most applicationsare diastereoselective including peptides as substrates [83].

were produced in 96 and 97% ee, respectively. The yields refer to the isolated anddistilled products [85].

The protocol was also applied to enantiomerically pure d-caprolactone (R)-55a andg-valerolactone (R)-55b. In the reactions the lithium enolate 56 generated from six-membered lactone (R)-55a with dimethylallyl carbonate 32b, a clear stereocontrol wasexhibited by the chiral catalyst (reagent control), and the inherent selectivity of thesubstrate is irrelevant (Scheme 14). Thus, the combinations of lactone (R)-55 with (R)-and (S)-BINAP (33) lead to the different diastereoisomers 57 and 58. In both cases, thediastereoisomer ratio (dr) amounts to 97 :3, defined as the ratio of the majordiastereoisomer to the sum of the three others. Both products 57 and 58 areenantiomerically pure, but, of course, not enantiomeric, as evident from the CDspectra, also included in Scheme 14. Various unsuccessful attempts were made to obtaina crystalline derivative of either lactone 57 or 58 in order to determine the relative


Scheme 14. Reagent Control in the Reaction of Lactone (R)-55 with Dimetylallyl Carbonate 32b viaLithium Enolate 56. CD Spectra of products 57 and 58, and crystal structure of metathesis-product of

lactone 57 are also shown.

configuration at the newly created stereogenic centers by means of a crystal structureanalysis. Finally, lactone 57 was submitted to a cross-metathesis with 4-bromostyrene.The crystal structure of the corresponding alkene, shown in Scheme 14, unambiguouslyreveals the relative configuration [85].

The reaction of the six- and five-membered lactone (R)-55a and (R)-55b,respectively, with allyl carbonate 32c, mediated with (R)- and (S)-BINAP (33) servedus as an experimental base (Table) for theoretical calculations that were performed byThiel and Patil [85] [86] and aimed at rationalizing the observed topicity in theselectivity-determining step. When the allylation protocol was applied to (R)-configured d-caprolactone 55a, a control occurred to a wide degree, and thediastereoisomers trans-59a and cis-60a formed predominantly, depending on whichenantiomer of the chiral ligand at the Pd has been chosen, albeit the degree ofdiastereoselectivity is slightly different (5 : 95 vs. 87 : 13; Table, Entries 1 and 2). Whenthe five-membered lactone (R)-55b was submitted to the standard protocol with allylcarbonate 32c, mediated again by the enantiomers of the BINAP ligand 33, a clearmatched�mismatched situation resulted: the low dr 59b/60b in the combination of (R)-lactone 55b with (R)-BINAP indicated an antagonistic effect of the chiral information.The significant higher predominance for the trans-diastereoisomer 59b resulting fromthe (R)-lactone�(S)-BINAP combination indicates that the inherent preferences ofthe substrate16) and the chiral catalyst are cooperative (Entries 3 and 4).

Based upon these experimental data, DFT calculations were first performed for theallylation of the five-membered lactone (R)-55b, in order to study the mechanism,while a focus was put on the role of LiCl. In the B3LYP-I approach, the geometries and


Table. Experimental and Calculated Diastereoselectivities of Lactones 59 and 60 Obtained by AllylicAlkylation of (R)-55

Entry Lactone n Ligand Exper. diastereo-selectivity (dr)trans-59/cis-60

Calc.a) diastereo-selectivity (dr)trans-59/cis-60

1 (R)-55a 2 (R)-33 5 : 95 2 : 982 (R)-55a 2 (S)-33 87 : 13 90 : 103 (R)-55b 1 (R)-33 56 : 44 62 : 384 (R)-55b 1 (S)-33 91 : 9 90 : 10

a) Calculated diastereoisomer ratios obtained from the free-energy differences of the two diastereoiso-meric transition states, computed at the B3LYP-IV level.

16) A dr 59b/60b of 75 : 25 has been reported to result from the non-catalyzed reaction of the lithiumenolate at � 788; see [87].

the relevant minima and transition states-energie were fully optimized. The effect ofthe solvent was considered by the polarizable continuum model (PCM). At theB3LYP-II level, empirical dispersion corrections were included by single-pointcalculations at B3LYP-I geometries. The B3LYP-III and B3LYP-IV results wereobtained analogously by using gas-phase optimized geometries. The calculations on g-lactone 55b took into account three enolate structures: the ion pair 61a with thenegative charge delocalized, the O-bound tautomer 61b, and, upon addition of LiClchloride, the mixed aggregate 61c. Concerning the relevant Pd complexes, aside fromthe [(h3-C3H5)Pd-(S)-BINAP] cation 62a, the complexes [(h3-C3H5)PdCl-(S)-BINAP](62b) and [h1-C3H5)PdCl-(S)-BINAP] (62c) were considered as the reactive species(Fig. 9).

By combining the individual structures of 61 and 62, five different pathways for thenucleophilic addition of the enolate to an allyl-Pd complex were calculated, and therelevant transition states were located. Among the different permutations, only thecombination of the mixed aggregate 61c with the h3-complex 62b, wherein chloride is


Fig. 9. Calculated transition state 63 for the allylic alkylation of the lithium enolate of (R)-g-valerolactone55b mediated by (S)-BINAP: visualization of the outer-sphere mechanism

bound directly to palladium predicted the trans-configured allylated lactone 59b to beformed as the major product, as it was found in the experiment (cf. Table, Entry 4).Moreover, the transition state leading to trans-lactone 59b has the lowest free energy ofall the transition states considered. The calculated product ratio of trans-59b/cis-60bamounts to 90 : 10 and is in an excellent agreement with the experimental trans/cisselectivity of 91 : 9. Thus, is was concluded that the outer-sphere pathway through thetransition state as shown by the model 63 shown in Fig. 9 is the most likely route for thenucleophilic addition step in the Pd-catalyzed allylic alkylation, at least in the presenceof LiCl. The approach of the enolate is directed by stabilizing electrostatic Li�Cl andLi�O interactions. The �Li2O2� moiety (Fig. 9) makes the enolate more bulky at the oneend, thus causing discrimination between 63 and a diastereoisomeric transition state.The fact that the enolate approaches to the ally moiety from the face opposite to thetransition metal is provided by a �tether� consisting of Cl-atom bound to Pd and theLi2O2-square linking the transition metal to the enolate [85].

Analogous calculations were performed for the combination of the aggregate 61cand the Pd complex 62b with (R)-BINAP ((R)-33) as the chiral ligand and resulted in aprediction of a trans-59b/cis-60b distribution of 62 : 38 – again in almost perfectagreement with the experimental results (Table, Entry 3). Finally, the calculations wereextended to a Li�Cl aggregate of the six-membered lactone enolate (analogous to 61c),again with the Pd complex 62b and (R)- and (S)-33. The results, given in Entries 1 and 2of the Table, again show an excellent agreement between calculated and experimentaldata. The accordance for all the four combinations of Table clearly underlines thereliability of the DFT calculations. In summary, it became evident from this study alsothat the Pd catalyzed allylic alkylation of preformed lithium enolate follows the outer-sphere mechanism [86].

Finally, we tackled the Pd-catalyzed allylic substitution of doubly deprotonatedcarboxylic acids. In view of the fact that the pKa value of acetate was determined as 33.5[88], the dianions of carboxylic acids can be classified as �hard� enolates without anydoubt. In synthesis, the Mg derivatives of a-aryl carboxylic acids, ArCH¼C(OMgX)2,the so called Ivanov reagents [89], as well as the more generally applicable dilithiatedspecies R2C¼C(OLi)2 64 (R¼ aryl, alkyl, and H) were applied. The latter nucleophilicreagents were disclosed by Creger [90], and improved, more convenient protocols fortheir generation were reported by Mulzer et al. [91] and, more recently, by Parra et al.[92].

Application of our standard protocol to doubly lithiated carboxylic acids 64 showedthat the Pd-catalyzed allylic alkylation is feasible without problems even with this typeof lithium enolates. Remarkably, the procedure cannot only be applied to a-aryl-substituted carboxylic acids but to mono- and even dialkyl-substituted ones as well.Indane-1-carboxylic acid is also a suitable substrate. Dimethylallyl carbonate 32b, aswell as allyl carbonate 32c, served as substrates. Illustrative examples including theisolated yields of 65 are compiled in Scheme 15. As in that preliminary study, wefocused on the feasibility of the conversion rather than on stereoselectivity, racemicBINAP (33) was mostly used as the chiral ligand at Pd [93].

A diastereoselective and enantioselective version was elaborated for 2-phenylaceticacid. In this case (S)-Cl-MeO-BIPHEP 37 served as the chiral ligand at the transitionmetal, and dimethyallyl carbonate 32b was used as substrate. Hex-4-enoic acid 66 was


obtained in fair diastereoselectivity in favor of the anti-diastereoisomer, which formedin substantial ee. The chemical yield refers to the isolated anti-diastereoisomer 66(Scheme 15) [93].

A final, preliminary result concerns the allylic alkylation of simple carboxylic acids– considered by us as seductive and, at the same time, challenging (Scheme 16). Thechallenge arises from the nature of doubly lithiated acetic acid – probably a highlyaggregated species, whose mixture in THF has a milky consistence, and reactions wereexpected to be sluggish17). The approach is on the other hand seductive, because it isthe straightforward alternative to the traditional Tsuji�Trost protocols using malonatesand degrading the allylation products to alkenyl monocarboxylic acids by saponifica-tion and decarboxylation. Obviously, both approaches end up with the same type ofproducts.

Thus, dilithiated acetic acid 67 was generated according to the protocol of Parra andco-workers [92] using 2 equiv. of BuLi but only 0.6 equiv. of (iPr)2NH. Application ofthe allylation procedure with dimethyallyl carbonate 32b and LiCl gave 3-methylhex-4-enoic acid (69), however, in poor yield and contaminated with various side-products,which seem to result from substitution at the carbonyl group of carbonate 32b.


Scheme 15. Pd-Catalyzed Allylic Alkylations of Doubly Lithiated Carboxylic Acids. Diastereoselectiveand enantioselective synthesis of hex-4-enoic acid 66

17) Based upon early calculations, a structure of dilithiated acetic acid was postulated to feature one Liatom rebound to the C¼C bond [94]. More recent calculations, however, present more conventionalstructures for dilithiated carboxylic acids [95].

Considering different leaving groups at the allylic substrate, we turned to �dimethylallylchloride� 32d to avoid interference of the dilithium reagent 67 with the leaving group. Inaddition, it has the advantage to serve as a source for LiCl which forms gradually as thereaction proceeds. Indeed, hex-4-enoic acid (S)-69 was obtained in 78% isolated yield.An ee of 88% was reached, when (S)-68 was used as the chiral ligand. The loading ofthe catalyst, 0.5 mol-% of both ligand and Pd, is remarkably low [96]. Furtherexperiments with different allylic substrates will reveal scope and limitations of the�acetate allylic alkylation�. When, according to this protocol, �dimethylallyl chloride�32d and (R)-BINAP (33) were applied for the allylation of 2-phenylacetic acid (cf.Scheme 15), the dr in favor of ent-anti-66 was enhanced to 87 :13 and the ee to 91%[97].

Conclusions. – This review started with spotlights directed to selected seminalcontributions to the structure of lithium enolates. In the second part, recent syntheticapplications by the author�s group were presented that might be considered as beingjust another tessera in the enolate mosaic, but at least demonstrate the compatibility ofenolate and allyl-Pd chemistry – a generally accepted synthetic method today.

I am very grateful to Dr. Karl-Heinz Geiss for the photos. I would like to thank my enthusiastic co-workers, Dr. Frank Laicher, Dr. Thorsten Meier, Dr. Panos Meletis, Dr. Mesut Fidan, and Dipl.-Chem.Robin Visse, whose contributions to this field are highly appreciated. The support provided by theDeutsche Forschungsgemeinschaft is gratefully acknowledged.

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Scheme 16. Attempts at an Enantioselective �Acetate Allylic Alkylation�

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Received September 11, 2014


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