the renaissance of zinc carbenoid in stereoselective synthesis in acyclic systems

The Renaissance of Zinc Carbenoid in Stereoselective Synthesisin Acyclic SystemsMorgane Pasco, Noga Gilboa, Tom Mejuch, and Ilan Marek*

The Mallat Family Laboratory of Organic Chemistry, Schulich Faculty of Chemistry and Lise Meitner-Minerva Center forComputational Quantum Chemistry, Technion-Israel Institute of Technology, Technion City, Haifa 32000, Israel

ABSTRACT: In the last few decades we have witnessed therenaissance of zinc carbenoid in acyclic stereoselective synthesis.From the pioneering work of Simmons and Smith that led to amyriad of beautiful enantioselective cyclopropanations ofalkenes, zinc carbenoid is again at the center of interest, butthis time for the acyclic control of selectivity in allylationreactions. A straightforward method, utilizing the dualcharacteristics of zinc carbenoid serving both as an electrophileand as a nucleophile, has been recently developed for thepreparation of various 3,3-disubstituted allylzinc species thatreact with various carbonyl and imine moieties to givehomoallyl alcohols and amines, respectively, with very highdiastereoselectivity. In a one-pot operation, three new carbon−carbon bonds as well as two new sp3 stereogenic centers wereformed, including the formation of the challenging all-carbon quaternary stereogenic centers.

The term “carbenoid” appeared in the early 1960s to describea reactive intermediate possessing a carbon geminally

substituted with a metal and a leaving group that may act like acarbene.1,2 Carbenoid possesses highly polarized bonds and canbe represented by the general formula R1R2-CMX (1, whereM = metal, X = leaving group) with the central carbon showingboth a negative and a positive formal charge. If they undergo aα-elimination, M+ and X− are released to leave the free carbenemolecule 2 (Scheme 1).

However, the reactivity of carbenoid differs from that of tripletcarbene, as illustrated by the reaction of diphenyldibromomethane(3) with a solution of MeLi in the presence of either (Z)- or(E)-but-2-ene in diethyl ether at low temperature. 1,1-Diphenylcy-clopropane (4) was obtained with a complete preservation of thestereochemistry of the initial double bond.3 On the other hand,when the carbene 6 is generated, through photolysis of diphenyl-diazomethane (5), a mixture of cis- and trans-1,1-diphenylcyclo-propane was obtained (Scheme 2).4−7 Since these pioneeringworks, a large number of halolithiocarbenoids have been reported byKobrich and these species have found a tremendous interest in

synthesis due to their unique ambiphilic aspects, showing bothnucleophilic and electrophilic reactivities.8

Theoretical calculations performed on the simplest model ofcarbenoid LiCH2F showed that the most stable isomer is thelithium-bridged 7 with Li+ binding to both carbon and fluorine(inverted, “umbrella-shape” conformation about the carbon).9

The elongation of the C−F bond in 7, in comparison to the non-lithiated compound 8, is typical of a carbenoid structure and is

Received: December 19, 2012Published: January 24, 2013

Scheme 1. General Preparation of Carbenoid

Scheme 2. Carbene vs Carbenoid in the Formation of 1,1-Diphenylcyclopropane

Review

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consistent with a weakened bond and a high electrophilicity ofthese species. These findings were later confirmed by X-rayanalysis1 (Scheme 3). From a thermodynamic point of view,

α-elimination of LiF from the carbenoid LiCH2F (7) to give thefree carbene and LiF is very unfavorable in the gas phase. Theexperimental observations indicate that only carbenes with twodonor substituents are formed by α-elimination of LiX from thecorresponding carbenoid.10

The influence of the metal as well as the ancillary ligand interms of structure and reactivity is of paramount influence. Thezinc carbenoid, which has a high covalent character, is morestable and reacts more selectively than alkali-metal species. Thisproperty makes the zinc carbenoid a very attractive intermediatefor the chemo-, regio-, and enantioselective creation of cyclopro-panes.11 The two derivatives (iodomethyl)zinc iodide (9) and bis-(iodomethyl)zinc (10) are among the most popular carbenoidsand have been widely used for the Simmons−Smith cyclopropana-tion reactions of olefins. In the original report, the reagent wasprepared in situ from a zinc or zinc−copper couple anddiiodomethane.12 A few years later Furukawa reported analternative method to generate the carbenoid, by a halogen−metal exchange reaction between diethylzinc and diiodo-methane, which has the advantage of giving a rapid andhomogeneous reaction under mild conditions (Scheme 4).13

X-ray crystallographic analysis of the bis(iodomethyl)zinc(10) species shows that this reagent is stabilized by a proximaloxygen functionality14 and therefore the Simmons−Smithreaction with an allylic alcohol gives a higher reaction rate(ca. >1000 times in comparison to a simple olefin) with highstereocontrol. Calculations made by Nakamura revealed that themethylene transfer reaction takes place in two steps: first anSN2-like displacement of the leaving group by the olefin, followedby the cleavage of the C−Zn bond (Scheme 5).15

Since then, numerous highly enantio- and diastereoselectivecyclopropanation reactions have been described.16 The mostillustrative examples are described in Scheme 6.17

Zinc carbenoid has also been used differently through anelegant chain-extension reaction in which β-keto esters aretransformed into γ-dicarbonyl species. A tandem chainextension−aldol process has been applied to peptide isostere

formation and natural product synthesis.18 Recently, stereo-selective synthesis of a functionalized dipeptide isostere usingthis methodology has been reported (Scheme 7).19

Scheme 3. MP4SDTQ/6-31G*//HF/6-31G* Structure of theMost Stable Isomer LiCH2F (7) vs CH3F (8)

Scheme 4. Preparation of the Simmons−Smith−FurukawaZinc Carbenoid

Scheme 5.Mechanism of the Cyclopropanation Reaction withthe Simmons−Smith−Furukawa Zinc Carbenoid

Scheme 6. Selected Examples of the Diastereo- andEnantioselective Cyclopropanation Reactions of Alkenes

Scheme 7. Tandem Chain Extension−Aldol Reactions withZinc Carbenoid

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As summarized above, the chemistry of zinc carbenoids hasbeen mostly investigated for the diastereo- and enantioselectiveformation of cyclopropanes. However, is the ambiphilic nature ofzinc carbenoid only useful for the formation of three-memberedrings? In fact, zinc carbenoid could also be extremely useful in thehomologation reaction of organometallic species.20 In thisparticular process, the dual nature of the carbenoid would befully used, as it could lead to the formation of a new carbon−carbon bond with concomitant creation of the new organo-metallic species 11.20b The mechanism of this transformation hasnever been elucidated computationally but could be summarizedby either a SN2-type transformation with non-nucleophilicspecies (i.e., RCu, Scheme 8, path A, intermolecular homologation)

or through the initial formation of the ate complex 12whenmorenucleophilic species are used (i.e., RMgX, RLi) followed by a 1,2-shift of the carbon ligand R bound to the zinc (Scheme 8, path B,intramolecular homologation). If (iodomethyl)zinc iodide (9) isused for the intramolecular homologation reaction, an additional1 equiv of R-M1 may be necessary to first displace the halide onthe zinc atom before reaching the stage of zincate. Although 11is represented as a monomeric zinc species, it may be anorganometallic species of a different nature, obtained through anin situ transmetalation with M1-I salts present in the reactionmixture.The pioneering work of Knochel in this field was particularly

inspiring, as he could perform an homologation reaction ofvinylcopper 13 with 9 into the allylmetal species 14 at lowtemperature followed by an in situ reaction with a carbonylcompound (Scheme 9).21 Without the presence of this in situelectrophilic partner, the allylic species 14 undergo furtherreactions with (iodomethyl)zinc iodide (9) to lead to the double-homologated product 15 (the reactivity of allylzinc is higher thanthat of vinylcopper toward the zinc carbenoid and should betherefore trapped in situ).Why was it so inspiring? Simply because the combination of

the well-known carbocupration reaction of terminal alkynecoupled with the zinc-homologation reaction should lead to thestereoselective formation of γ,γ′-disubstituted allylzinc 16 speciesin a one-pot operation from simple alkyne. Addition of a carbonylmoiety as an electrophilic partner may lead to the formation of ahomoallylic alcohol with high diastereoselectivity if the γ,γ′-disubstituted allylzinc is configurationally stable. However, majorproblems usually arise with allylic organometallic derivatives(such as Li, Mg, Zn, Cu, etc.). Indeed, the correspondingsubstituted allylmetal species is configurationally unstable andleads to mixture of rapidly equilibrating E and Z isomers through

a haptotropic equilibrium.23 Therefore, the stereoselection ofsuch processes is usually low and remained extremely challengingfor the preparation of γ,γ′-disubstituted allylmetal species 16.This is why the control of the stereochemistry in carbonylallylation reactions has been well established for configuration-ally stable semimetallic reagents (such as those containing boron,silicon, and tin), allowing in some cases the formation of quaternarystereocenters, as the stereochemistry of the double bond usuallyrelates to the stereochemistry of the final adducts (the syn/antiratio relates to the Z/E ratio of the starting material when cyclictransition states are considered).22

Coming back to the γ,γ′-disubstituted allylzinc, it was clear thateven if one can prepare the expected polysubstituted allylmetalspecies 16 through this one-pot strategy, the metallotropicequilibrium should be slow as compared to the reaction with theelectrophiles (Scheme 9). Therefore, to increase the stability ofthe allylic organometallic species in its α-position, we thoughtthat an intramolecular chelation of the zinc atom by an A-B unit(Scheme 9) would be beneficial.Therefore, our initial proposed synthetic plan was based on

(1) the initial formation of a stereodefined β,β′-disubstitutedvinyl metal 18, easily obtained through a controlled carbocupra-tion reaction of substituted heterosubstituted alkynes 17 possess-ing a chelating and electron-withdrawing AB unit (Scheme 10),(2) a homologation reaction with zinc carbenoid leading to the insitu formation of the γ,γ′-disubstituted allylmetal species 19,intramolecularly stabilized by chelation with the A-B unit, and(3) reaction with a carbonyl compound, already present in thereaction mixture to give the diastereomerically enrichedhomoallylic alcohol 20. Obviously, if one wants to obtain theenantiomerically enriched homoallylic alcohols 21, the A-B unitshould be easily removed or functionalized.Considering these prerequisites, we designed alkynyl sulfoxide

22 as the ideal substrate.24 Various alkynyl sulfoxides were easilyprepared, in 70−80% yields, by the Andersen synthesis.25 Ourfirst investigation concerned the regio- and stereospecificcarbocupration of 22with organocopper reagent (easily obtainedfrom 1 equiv of alkylmagnesium halide and 1 equiv of CuX;X = Br, I), which provides the corresponding metalated

Scheme 8. Inter- vs Intramolecular Zinc Homologation

Scheme 9. Proposed Strategies and Potential Pitfalls



β,β′-dialkylated vinylcopper 23 in quantitative yields (Scheme 11).26Then, to the reaction mixture, aldehyde was added followed by

bis(iodomethyl)zinc carbenoid 10, independently prepared from1 equiv of Et2Zn and 2 equiv of CH2I2. Neither the vinylicorganocopper 23 nor the zinc carbenoid is reactive enough toadd to aldehydes. However, 23 is readily homologated with thezinc carbenoid 10 to generate in situ the reactive chelatedallylzinc species 24. The latter reacts diastereoselectively with thecarbonyl group to give, after hydrolysis, the correspondingadducts 25 in good overall yields and with excellent diastereo-selectivities (Scheme 11).24,27 It is interesting to note that thereaction proceeds similarly for aromatic and aliphatic aldehydes(25a−c and25d, respectively).As shownwith25a (R1=Et, R2 = Bu)and 25b (R1 = Bu, R2 = Et), permutation of the alkyl groups ofthe alkyne and the organocopper reagent allows theindependent formation of the two isomers at the quaternarycarbon center, respectively. Even methylcopper, known to bea sluggish group in the carbocupration reaction, adds cleanlyto the alkynyl sulfoxide 22 to give after the homologationallylation reactions the expected homoallylic alcohol as onlyone isomer (25c). By using this simple methodology, a chiralquaternary carbon center with two sterically very similar alkylgroups such as ethyl and methyl can be easily prepared as asingle isomer.The chiral sulfoxide moiety fulfilled all its duties, as it could

direct the regio- and stereoselectivity of the carbometalationreaction, it could slow down the metalotropic equilibrium of thein situ formed γ,γ′-disubstituted allylzinc species through intra-molecular chelation, and finally it could serve as a chiral inductorto differentiate the two prochiral faces of the allylzinc with thecarbonyl group.Although we were pleased that all these carbometalation−

homologation−allylation reactions led, with very high diaster-eoselectivity, to the corresponding homoallylic alcohol deriva-tives 25, the bis(iodomethyl)zinc carbenoid 10 had to be

prepared independently and further transferred into the reactionmixture at low temperature. To improve our reaction sequence,we developed an easier and more straightforward procedure.After the first step of carbocupration, aldehydes, Et2Zn, andCH2I2 were all added to the reactionmixture at−20 °C(Scheme 12).

As discussed previously, neither vinylcopper 23 nor Et2Zn reactswith aldehydes and vinylcopper also does not react with CH2I2,and as the transmetalation from vinylcopper to vinylzinc is a slowprocess at−20 °C, the reaction between Et2Zn and CH2I2 occursfirst to lead to the in situ formation of the zinc carbenoid 10(Scheme 4). Under these conditions the expected homoallylicalcohols 25 were obtained with similar diastereoselectivities ingood isolated yields (Scheme 12).27

As can be seen in Scheme 12, different alkyl groups on thequaternary stereocenter can easily be introduced in the finalhomoallylic alcohols 25, which shows the flexibility of thedescribed method. Functionalized aldehydes can also participatein this allylation reaction through chemoselective reactions. Whenthe two alkyl groups on the all-carbon quaternary stereocenterare identical, a 1,4-diastereoinduction was observed (formationof 25h,j,m). Finally, even heteroaromatic aldehydes can be usedas electrophilic partners in this reaction (25l−n). The absoluteconfigurations were assigned by X-ray analysis. This newapproach for the allylation reaction can even be further simplifiedby combining these steps into a real four-component reac-tion.28 In this case, one needs to prepare only an alkylcopperderivative. Indeed, alkynyl sulfoxide, benzaldehyde, Et2Zn, andCH2I2 are added simultaneously to the organocopper species inthe flask as described in Scheme 13.27

The absolute configurations of the products were determinedby X-ray crystallographic studies of 25a,c, and the configurationsof other reaction products were assigned by analogy (Schemes 11and 12). The observed final stereochemistry is rationalizedthrough a consequence of events as summarized below andillustrated in Scheme 14.

(a) The defined stereochemistry of the two alkyl groups onthe double bond results from the regio- and stereoselectivecarbocupration reaction (23).26,29

(b) The zinc homologation proceeds at low temperature andleads to the corresponding allylzinc species 24.21

Scheme 10. Complete Proposed Strategy

Scheme 11. Combined Carbometalation−Homologation−Allylation Reaction of Alkynyl Sulfoxides with Aldehydes

Scheme 12. One-Pot Homologation Reaction of AlkynylSulfoxides with Aldehydes



(c) The oxygen atom of the sulfoxide chelates the zinc andprevents the metallotropic equilibrium.30

(d) The nonbonding electrons of the sulfoxide group are synto the double bond to minimize the 1,3-allylic strain.31

(e) The aldehyde reacts with the γ,γ-disubstituted allylzincspecies 24 through a Zimmerman−Traxler transition stateand from the opposite side of the tolyl group.

(f) The R3 group of the carbonyl moiety occupies apseudoequatorial position.

The beauty of this approach relies on the complete control ofthe reactivity of each component present in this one-pot reaction(Schemes 11−13). However, for any extension towardasymmetric catalysis, it became crucial to decrease the numberof organometallic species present in the reaction mixture, and wetherefore developed a catalytic approach combining these foursimple precursors: alkynyl sulfoxide, (R2)2Zn, CH2I2, andaldehydes. The copper-catalyzed carbozincation of alkynylsulfoxide proceeds quantitatively at room temperature in THFto lead to the corresponding vinylalkylzinc species 26.32 WhenEt2Zn is used for the carbozincation step, the subsequentaddition of aldehydes and CH2I2 to the reaction mixture at −20°C leads to the expected homoallylic alcohols 25 in good isolatedyields and excellent diastereomeric ratios. In this case, instead ofhaving a zinc homologation through an intermolecular reactionbetween the sp2 organometallic species and the zinc carbenoid(Scheme 8, path A), the vinylalkylzinc 26 reacts first with CH2I2to give the corresponding vinyl(iodomethyl)zinc 27 with con-comitant formation of EtI. Then 27 undergoes an intramolecularzinc homologation (1,2-metal rearrangement33 similar tothat described in Scheme 8, path B) to give the allylzincspecies 24. Reaction with aldehydes then proceeds similarlyto lead to the corresponding homoallylic alcohols 25a,e(Scheme 15). However, when Me2Zn or BuZnBr was usedfor the copper-catalyzed carbozincation step (formation of25c,q, respectively), the in situ formation of zinc carbenoid is

slow and therefore a subsequent addition of a new 1 equiv ofEt2Zn is required to quantitatively form the carbenoid in thereaction mixture.The power of this strategy could be illustrated by the

preparation of substrates possessing challenging chiral all-carbonquaternary stereocenters such as the ones represented in Scheme 16.

For this purpose, we initially prepared 1,1,1-trideuteriopropynylsulfoxide and submitted it to our copper-catalyzed methyl-zincation reaction as described in Scheme 15. Once thecarbometalated product was obtained, Et2Zn, CH2I2, andbenzaldehyde were subsequently added to the reaction mixtureto lead to the expected homoallylic alcohol 25r with very highdiastereoselectivity (de 94% in 82% yield), as described inScheme 16. An even smaller difference for the creation of aquaternary center was achieved by using a labeled carbon atom.When commercially available 13CH3I was treated with Mg, theGrignard reagent 13CH3MgI was initially formed and wasconsequently transformed into its corresponding organocopperreagent 13CH3Cu. The carbocupration of this freshly preparedlabeled organocopper species was performed with propynylsulfoxide, and to the resulting vinylcopper species were addedEt2Zn, CH2I2, and benzaldehyde. Homoallylic alcohol 25s wasobtained in 60% yield and 95% diastereomeric excess (Scheme16). The diastereoselectivity of these reactions could easily bedetermined on the crude NMR product (the two parent Megroups are diastereotopic), but the absolute configurations werededuced by analogy from all our previously prepared homoallylicalcohols.

Scheme 13. Four-Component Reaction for theDiastereoselective Synthesis of Homoallylic Alcohols in anAcyclic System

Scheme 14. Proposed Transition State for the Reaction ofAllylzinc with Aldehydes

Scheme 15. Toward Catalytic Processes

Scheme 16. Application to the Formation of Challenging All-Carbon Quaternary Stereogenic Centers



In all the chemistry we have developed so far, the chiral sulfinylgroup played an unique role, as it could control theregioselectivity of the carbometalation reaction and the metal-lotropic equilibrium and finally induce a diastereofacial choice inthe allylation reaction. However, for any further syntheticapplications, sulfoxide must be disposed of at the end of thesequence, as it should only be a chiral synthetic tool. Among allthe possible methods, the sulfoxide−metal exchange reaction is avery interesting transformation, since it leads to the formationof a new vinylmetal species that can be further functionalized.In this context, we have recently reported that E- andZ-heterosubstituted alkenes such as enol ethers,34 silylenolethers,34 vinyl sulfides,35 vinyl sulfoxides,35 vinyl sulfones,35 andvinyl carbamates36 were excellent candidates for the stereo-selective formation of vinyl-37,38 and dienylmetal39 species. Inthis particular case, the fastest and most efficient sulfoxide−metalexchange reaction was obtained when homoallylic alcohols25a,m were first treated with MeLi (initial deprotonation of thealcohol) and then with t-BuLi in Et2O at −78 °C.40 Thecorresponding vinyllithium species 28a,m were obtained, via thissulfoxide−lithium exchange reaction, in excellent yields asdetermined after acidic hydrolysis (Scheme 17). The enantio-

meric ratio (er) of 29 and 30 (96/4) was determined by analysisof chiral HPLC (chiral column Chiralpak AD-H) and was foundto be similar to the enantiomeric ratio of the starting alkynylsulfoxide 22 (er = 96/4). Vinyllithium can also react with electro-philes to give functionalized adducts (see 31 as a representativeexample obtained by addition of I2).To further extend this new approach to the creation of

quaternary stereogenic centers, an alternative method, no longerbased on intramolecular chelation from the substrate but ratheron intermolecular chelation through an external ligand, wasdeveloped. Among all the possible sources of external chiralligands, the substrate-induced stereoselectivity using chiralsulfinylimines as electrophiles was tested.41 Indeed, the Ellman’senantiopure (R)-N-tert-butanesulfinimine42 (Scheme 18) couldbe utilized as a chiral nitrogen intermediate for the preparation ofa wide range of chiral amines. In our specific context, anintermolecular stabilization of the 3,3-disubstituted allyzincspecies by the sulfinimine is needed to avoid the metallotropicequilibrium. In the first approach, disubstituted vinyl iodides 32,easily prepared by carbocupration reactions of alkynes,29 weretreated with t-BuLi in THF at −78 °C, followed by addition of1 equiv of CuI to lead to the corresponding vinylcopper 33 at−30 °C. To the resulting vinylcopper derivatives were

consequently added Et2Zn, CH2I2, and various sulfinimines togive the expected homoallylic sulfinylimines 34 (Scheme 18).43

In all cases, excellent diastereoselectivities and chemical yieldswere obtained, whatever the aliphatic substituents on the startingalkenes. Functionalized aromatic imines are also compatible inthis reaction, as the allylzinc species reacts chemoselectively(Scheme 18, 34d,e). As the E conformation of thesulfinylimine should be maintained (high rotational barrierof 41.3 kcal mol−1), a closed Zimmerman−Traxler transitionstate would push the substituent of the sulfinylimine in apseudo-axial position, as described in Scheme 18.43 Moreover,the sulfinylimine should adopt a conformation in which theSO bond and the lone pair of electrons on the nitrogenatom are antiperiplanar, mainly as a result of a significant nN→S*SO negative hyperconjugation interaction.44 Therefore,the 3,3-disubstituted allylzinc species react with the imine antito the bulky substituent t-Bu.As sulfinylimine has a lone pair, chelation with an organo-

metallic species could therefore be envisaged and change thestereochemical outcome of a process through chelation control.From a conformation in which the SO bond and the lone pairof electrons on the nitrogen atom are antiperiplanar, addition ofmetallic salts should be able to give a chelated model, asrepresented in Scheme 19.6b,30b

The outcome of this chelated model is that, for the sameabsolute configuration of the sulfinylimine, the bulky t-Bu group

Scheme 17. Sulfoxide−Lithium Exchange

Scheme 18. Preparation of Homoallylic Sulfinamines 34 fromVinyl Iodide

Scheme 19. Antiperiplanar to Chelated Model



shields now the opposite face and therefore the diastereose-lectivity of the incoming nucleophile should be opposite. To testthis hypothesis, we decided to perform the reaction directly froman alkyne via an initial carbocupration reaction with analkylcopper generated from an alkylmagnesium halide and acopper salt that generates magnesium salts in situ. Then, to theresulting vinylcopper species were added our classical Et2Zn,CH2I2, and the same configured (R)-sulfinylimines at lowtemperature. We were pleased to see that not only does thisreaction lead to the homoallylamines 35 in good isolated yieldsand diastereomeric ratio but also indeed the oppositediasteromer is formed, as described in Scheme 20.43 It isimportant to note that even aliphatic sulfinylimine leads to theexpected adduct with excellent diastereomeric ratio (formationof 35c; Scheme 20).45

Both diastereoisomers of the all-carbon quaternary stereo-genic center, 35e,f, could be obtained only by permuting thenature of the two alkyl groups on the alkyne and on the copperspecies. After acidic hydrolysis of the sulfinamines, enantiomers34a and 36a were both obtained (Scheme 21).In the last few decades we have witnessed the renaissance of

zinc carbenoid in acyclic stereoselective synthesis. From thepioneering work of Simmons and Smith that led to a myriad ofbeautiful enantioselective cyclopropanation of alkenes, zinccarbenoid is again at the center of interest, but this time for theacyclic control of selectivity in the allylation reaction. Thisstraightforward method for the preparation of various 3,3-disubstituted allylzinc species was recently investigated in detailby our research group.46 This method utilizes the dualcharacteristics of the zinc carbenoid, potentially serving both asan electrophile and as a nucleophile. In situ prepared zinccarbenoid allowed the selective homologating reaction of a large

variety of vinyl metal species through its electrophilic properties.Once this stereodefined allylzinc species was formed, it couldreact with various carbonyl and imine moieties to give homoallylalcohols and amines, respectively, with very high diastereose-lectivity. In a one-pot operation, three new carbon−carbonbonds as well as two new sp3 stereogenic centers were formed,including the formation of the challenging all-carbon quaternarystereogenic center.47 There is no doubt that the power of zinccarbenoid in stereoselective synthesis will continue to grow andadditional beautiful synthetic transformations will continue toappear.

■ AUTHOR INFORMATIONCorresponding Author*E-mail: [email protected] authors declare no competing financial interest.Biographies

Morgane Pasco, born in Paris in 1984, studied chemistry at the EcoleNationale Superieure de Chimie de Paris (ENSCP-ParisTech), whereshe obtained a Master’s degree in 2007. She received her Ph.D. in 2010in the field of diversity oriented synthesis of polysubstituted amino-cyclopentanes under the direction of Dr. Laurent Micouin at ParisDescartes University. Then she moved to the laboratory of Prof. IlanMarek (Haifa, Israel) for a postdoctoral position, where she worked on anew route to access stereodefined trisubstituted enolates for theformation of quaternary stereogenic centres in acyclic systems. SinceSeptember 2012 she joined the University of Montpellier (France) as ashort-term teaching and research assistant in the group of Prof. JeanMartinez to work in the field of asymmetric synthesis toward modifiedamino acids.

Scheme 20. Preparation of Homoallylic Sulfinamines 35through Chelated Model

Scheme 21. Formation of the Two Enantiomers ofHomoallylic Amines



mailto:[email protected]

Noga Gilboa, born in 1979 in Moshav Balfuya, Israel, completed herundergraduate studies at Bar-Ilan University in Medicinal Chemistry in2006 (CumLauda). In 2006, she joined the research group of Professor IlanMarek initially as a Master student and rapidly moved to the direct Ph.D.program. Noga Gilboa graduated as Doctor of Philosophy in Chemistry in2012 for a thesis on “Preparation and Stereochemistry of HomoallylicAlcohols Containing Quaternary Stereocenters”. During her studies Nogareceived several awards, including the Jacobs and Gutwirth Awards.

Tom Mejuch was born in 1983. In 2006 he received his B.A. degree inMolecular Biochemistry program at the Schulich Faculty of Chemistry at theTechnion. In 2008 Tom received his M.Sc. degree (Cum Laude) at theSchulich Faculty of Chemistry, Technion, under the supervision of Prof.EhudKeinan, on the thesis entitled “Corannulene-based Synthetic ChemicalCapsids”. In 2008 Tom started his Ph.D. research under the supervision ofProf. IlanMarek. The title of his doctorate is “New andEfficientMethods forthe Preparation of Quaternary Stereocenters”. Aside from research, Tom’shobbies are music, languages, reading, traveling, fishing, and sports.

Ilan Marek is Professor of Chemistry at the Schulich Faculty ofChemistry at the Technion-Israel Institute of Technology. Since 2005,

he has held the Sir Michael and Lady Sobell Academic Chair and is aFellow of the Royal Society of Chemistry (FRSC). He was educated inFrance and received his Ph.D. thesis in 1988 from the University Pierreet Marie Curie, Paris (France), with Prof. Jean F. Normant. After a oneyear period as postdoctoral fellow in Louvain-la-Neuve (Belgium) withProf. Leon Ghosez, he obtained a research position at the CNRS(Centre National de la recherche Scientifique) at the University Pierre etMarie Curie in 1990. After obtaining his Habilitation in OrganicChemistry, he moved to the Technion-Israel Institute of Technology.He has been visiting Professor at the University de Montreal, Quebec(Canada), University Louis Pasteur, Strasbourg (France), UniversityParis-Descartes, Paris V (France), California Institute of Technology(CalTech), Pasadena, CA (USA), and the Ecole Nationale Superieurede Chimie de Montpellier (France).

Prof. Marek has received several awards for his research, including theFirst French Chemical Society-Acros Price for young Organic Chemist(under 40 years old in 1997), the Japan Society for the Promotion ofScience Visiting Professor Award (1997), the Lawrence G. HorowitzCareer Development Chair (1998), the Yigal Alon Fellowship (1998),Evelyn and Salman Grand Academic Lectureship-USA (1998), theYosefa and Leonid Allschwang award, administered by the Israel ScienceFoundation (2000), the Michael Bruno Memorial Award 2002,administered by the Rotschild Foundation (2002), the Prize forExcellent Young Chemist, The Israel Chemical Society (2004), theMerck Sharpe and Dohme Lecturer (2005), the Bessel Award of theHumboldt Foundation, Germany (2007), the Taub Award for AcademicExcellence (2009), The German-Technion Award for AcademicExcellence (2010), the Royal Society of Chemistry OrganometallicAward from the RSC (2011), the Taiwan National Science CouncilVisiting Scholar (2011), the Janssen Pharmaceutica Prize for Creativityin Organic Synthesis (2012), and the Israel Chemical Society Award forExcellence (2012). In addition to his recent and past achievements inresearch, he also had excellent achievements as a lecturer, expressed bythe five awards he received for excellence in teaching.

He is a member of the International Scientific Committee of EuropeanSymposium on Organic Chemistry (ESOC), including the position ofChairman (2007−2009), is currently the chairman of the division oforganic chemistry, European Association of Chemical and MolecularSciences (EuCheMS), a member of the advisory boards of ChemicalCommunications (RSC), Organic and Biomolecular Chemistry (RSC),European Journal of Organic Chemistry (Wiley), and Chemical Record(Wiley). He is also Associate Editor of the Beilstein Journal of OrganicChemistry, of the Israel Journal of Chemistry, and of the Patai series.

■ ACKNOWLEDGMENTS

This research was supported by the Israel Science Foundation.administrated by the Israel Academy of Sciences and Humanities(140/12). I.M. is holder of the Sir Michael and Lady SobellAcademic Chair.

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the renaissance of zinc carbenoid in stereoselective synthesis in acyclic systems

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