Zirconocene-Mediated Selective CâC Bond Cleavage of Strained

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Zirconocene-Mediated Selective C-C Bond Cleavage of Strained Carbocycles: Scope and Mechanism Jeffrey Bruffaerts, Alexandre Vasseur, Sukhdev Singh, Ahmad Masarwa, Dorian Didier, Liron Oskar, Lionel Perrin, Odile Eisenstein, and Ilan Marek J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b03115 • Publication Date (Web): 14 Mar 2018 Downloaded from http://pubs.acs.org on March 16, 2018

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The Journal of Organic Chemistry

Zirconocene-Mediated Selective C-C Bond Cleavage of Strained Carbocycles: Scope and Mechanism Jeffrey Bruffaerts,a‡ Alexandre Vasseur,a‡ Sukhdev Singh,a Ahmad Masarwa,a Dorian Didier,a Liron Oskar,a Lionel Perrin,*b Odile Eisenstein,*c Ilan Marek*a a

The Mallat Family Laboratory of Organic Chemistry, Schulich Faculty of Chemistry and Lise Meitner-Minerva Center for Computational Quantum Chemistry, Technion-Israel Institute of Technology, Haifa 3200009, Israel. b

Université de Lyon, Université Claude Bernard Lyon 1, CPE Lyon, INSA Lyon, ICBMS, CNRS UMR 5246, Equipe ITEMM, Bât. Curien, 43 Bd. du 11 Novembre 1918, 69622 Villeurbanne, France. c

Institut Charles Gerhardt, UMR 5253, CNRS-UM-ENSCM, Université de Montpellier, cc 1501, Place E. Bataillon, 34095 Montpellier, France. KEYWORDS. C-C bond cleavage – allylic C-H bond activation – remote functionalization – organozirconium – quaternary carbon stereocenters – DFT calculations

ABSTRACT: Several approaches using organozirconocene species for the remote cleavage of strained three-membered ring carbocycles are described. -Ene polysubstituted cyclopropanes, alkylidenecyclopropanes, -ene spiro[2.2]pentanes and -ene cyclopropyl methyl ethers were successfully transformed into stereodefined organometallic intermediates allowing an easy access to highly stereoenriched acyclic scaffolds in good yields and in most cases excellent selectivities. DFT calculations and isotopic labeling experiments were performed to delineate the origin of the obtained chemo- and stereoselectivities, demonstrating the importance of microreversibility.

1. INTRODUCTION Initiated by the pioneering work of Breslow1 and defined by Schwarz,2 the concept of remote functionalization – consisting in an initial interaction of a functional group with a reactant leading to a selective reaction at a distal position has increasingly been regarded as a cornerstone to alternatively solve challenging problems in organic synthesis.3 This indirect activation of a site distant from the initial functional group allowing the relay of chemical information across a molecular backbone strongly modifies our perception of retrosynthetic analysis. Not surprisingly, this concept has already sparked the development of numerous innovative transformations and nowadays represents a vibrant field of activity.4 Among those, transition-metal based methodologies, and more particularly metal-assisted alkene isomerizations across a hydrocarbon chain, have played a preponderant role in popularizing this conceptual approach.5,6 This property can be harnessed for the development of powerful tandem, cascade or sequential reactions involving a site distant from the initial double bond.7 An additional inherent advantage of such “zipping” process8 is that the chemical outcome is usually independent from the position and geometry of the initial double bond. Therefore, reactions involving even geometrical or positional mixture of olefins should converge towards the same product, as the unsaturation is used as a versatile chemical handle to trigger a chain of events leading to a predetermined termination site. As alkenes are ubiquitous motifs in organic chemistry, re-

mote functionalization via transition-metal assisted olefin isomerization represents a highly promising synthetic tool. 9 Among directionally selective alkene isomerization reactions, Negishi initially showed that treating an olefin with a low-valent zirconocene reagent (Cp 2ZrC4H8)10 efficiently enabled its long-range migration across methylene chains, to, in this case, provide a conjugated diene (Scheme 1, part I).11 This migration reaction, promoted by the later called Negishi reagent, was shown to occur through rapid and successively reversible allylic C-H bond activations. Later, we reported the zirconocene-mediated transformation of unsaturated fatty alcohol derivatives into allylzirconocene species (Scheme 1, part II).12 In this case, the isomerization (process also called Zr-walk or Zr-promenade) was driven by the β-alkoxide elimination step. It should be stressed that neither the double-bond geometry (E or Z) nor its relative position towards the alcohol affects the chemical outcome. This tandem isomerization-elimination reaction was also successfully applied to transform ω-ene enol ethers into stereodefined polysubstituted conjugated (E,Z)-dienyl zirconocene derivatives.13 Following these works, we anticipated that the release of a ring strain, provided by the selective ring opening of a three-membered carbocycle 14 might also provide a sufficient driving force for the desired bidirectional zirconocene alkene-migration. In parallel, numerous and various strategies have been developed to prepare diverse cyclopropane moieties with excellent levels of stereocontrol.15 Reckoning on their straightforward preparations,

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steroid (Scheme, part IV).18a Notably, such synthetically challenging motifs (1,4–stereocenters adjacent to an (E)– olefin) may also be found in natural products, such as botryococcene derivatives.19 In this Article, we wish to report an extension of these initial findings to fully probe the scope and mechanism of these unique transformations in the context of stereoselective synthesis (Scheme 1, part V). Furthermore, such unique reactivity raised several fundamental mechanistic questions, herein addressed through both experimental and theoretical studies.

we envisioned them as precursors to acyclic systems bearing stereocenters through selective C–C bond cleavage. This seemingly indirect strategy would constitute a valuable new tool to access challenging acyclic organic synthons, featuring for instance all–carbon quaternary stereocenters, 16 with high stereocontrol.17 In particular, seminal works18 already established the efficient zirconocene insertion into vinylcyclopropane (Scheme 1, part III) and its synthetic utility was further demonstrated through the stereoselective construction of the motifcontaining acyclic side chain of an active metabolite of a

Scheme 1. Illustration of several zirconocene–assisted transposition of olefins and their synthetic applications

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2. RESULTS AND DISCUSSION However, to achieve such zirconocene–mediated selective and remote cleavage, many issues need to be solved and pitfalls to be circumvented. Remarkably, the formation of, for example the acyclic product 2 from 1, relies on the perfect control of a cascade of events (Scheme 2). More specifically, the reaction of 1 with the Negishi reagent would provide the metal–alkene complex I (with n = 1 and m = 0 for the sake of simplicity) that would be required to successively undergo the following sequence: (i) an efficient migration of the double bond to reach the vinyl position of the cyclopropane II; (ii) a selective ring–opening leading to III; (iii) selective reactions with two different electrophiles leading to 2. The first issue of the proposed sequence lies in the directionality of the unsaturation migration, as the formation of the thermodynamically more stable organometallic compound V should be prevented. If the metal migrates towards the cyclopropane ring, two possibilities might arise for the carbocycle metal insertion. A C1–C3 bond cleavage would provide III whereas the cleavage of the C1–C2 bond

would give VI. If one still assumed that the C–C bond cleavage would be selective (i.e. unique formation of III), then the issue of configurational stability of the sp3 C1–[M] of the metalacyclobutane III would become of crucial importance for the diastereoselectivity of the reaction. One additional issue would be the site selectivity for the reaction with different electrophiles. Would III first react through the C1– [M] or C3–[M] bond (formation of IV vs. VII)? Supposing that the site selectivity would be controlled (i.e. reaction of III with the first electrophile via the allylic C1–[M] bond), then the mode of reactivity would also need to be controlled. Would it provide VIII or IV? Could the addition of the electrophile be stereoselectively? Which geometry would the resulting olefin adopt? Could the remaining organometallic species IV be further functionalized with a second electrophile? All these potential synthetic pathways and pitfalls stress the overall difficulty to selectively achieve such strategy.

Scheme 2. Illustration of all plausible intermediates for the metal–mediated conversion of 1 into 2.

terminal –bond of the substrate was thus investigated using but–1–ene as model substrate and DFT(M06) calculations with implicit SMD solvation (Et2O) (Scheme 3). This reaction is driven by the strong negative charge that is located at the  carbons of the butyl groups in c1. An intramolecular –H abstraction, (best viewed as a proton transfer) from one of the two butyl groups by the  carbon of the other ligand and subsequent elimination of butane (TS c2, ∆G‡ = 23.4 kcal mol-1) yields the Negishi reagent Cp2ZrC4H8

2.1. DFT Calculations. Initially, one of the first issues that we wanted to clarify was the original formation of the zirconacyclopropane obtained by treating an olefin with the Negishi reagent (Scheme 3). In the literature, a direct ligand exchange reaction is generally postulated 20 although a stepwise mechanism of addition–elimination was also suggested.21 Surprisingly, this event had never been previously computationally examined. The mechanism by which the zirconocene is transferred from the Negishi reagent to the



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shift allows the rotation of Cp2ZrH relative to the allyl group. Return to the 3–mode and reinsertion of the allyl group into the rotated Zr–H bond formally yields a –C=C bond shifted by a methylene group. Through this mechanism, zirconocene walks in the two directions along the carbon backbone. E/Z isomerization combines the above sequence and a rotation about the single C–C bond of the 1–coordinated allyl complex. Return to the 3–mode and reinsertion of the allyl group into the rotated Zr–H bond yield the isomerized E/Z olefin complex. The same E/Z isomerization operates the re to si face exchange. In the latter case, the initial C–H bond activation has to be performed on an allylic –cis conformation. These transformations therefore involve numerous elementary steps whose transition states are low in energy (G≠ < 15 kcal mol– 1 with respect to separate reactants Cp 2ZrC4H8 and but–1– ene) and all of similar energy (G≠ < 7 kcal mol-1). The combination of these previous sequences, that have common intermediates and similar energy profiles, allows the Scheme 3. Computed reaction pathway by which the coordination of zirconocene to all carbons without conforzirconacyclopropanes is transferred to an external mational restriction. The Gibbs energy profiles for these isomerizations are shown in Figures S2 to S4 in the SI. alkene

c3. An NBO population analysis revealed that the charge on Zr remains almost unchanged during this step. This shows that the formal oxidation state of Zr remains unchanged from c1 to c3 and that the zirconocene complex Cp 2Zr(2– H2C=CHEt) should be viewed as a zirconacyclopropane [Zr(IV)]. The formal alkene exchange is a two-step process that starts with a carbozirconation reaction [insertion of the C=C double bond of the incoming alkene into the Cp2ZrC4H8 drawn as a zirconacyclopropane in Scheme 3, following the transition state represented in c4 to yield the zirconacyclopentane intermediate c5. The formation of the final zirconacyclopropane is achieved by a ring– fragmentation with the release of but–1–ene from c5.22 The free energy barrier for this exchange reaction is moderate, and the irreversibility of the reaction is driven by the volatility of but–1–ene. It should be emphasized that the zirconacyclopropane character of c3 prevents a direct alkene exchange towards c3’.23

Figure 1. Free Gibbs energy profile (in kcal mol-1) for the Zr–walk: (i) switch of prochiral faces (ii) and (iii) isomerization of stereochemistry.

After studying the transfer of the Negishi reagent to an external alkene, we then examined the migration of the zirconacyclopropane along the carbon skeleton. During this migration, three types of isomerization were identified for pent–1–ene as model substrate: (i) zirconacyclopropane walking along a –trans skeleton, (ii) facial interconversion of the zirconacyclopropane via the –cis allylic intermediate, (iii) E to Z double bond isomerization i.e. syn/anti allyl isomerization (Figure 1). The initial coordination of electron deficient zirconocene to the  C=C double bond promotes the activation of the allylic C—H bond. This yields a zirconocene hydride 3–allyl complex, which is the pivotal intermediate to the dynamics of this complex. This equilibrium between the zirconacyclopropane and allyl–hydride complexes enables the Zr–walk (Figure 1). Starting from the most stable 3–allyl binding mode, a 3– to 1–haptotropic

2.2. Reactivity of ω–ene–cyclopropanes. In parallel, we experimentally started by investigating the reactivity of ω– ene–cyclopropane 1a (with two identical groups; R1 = R2) into acyclic product 2a by addition of the Negishi reagent Cp2ZrC4H8,10 freshly prepared from Cp2ZrCl2 and 2 equivalents of n–BuLi at low temperature in Et2O as solvent (Scheme 4). We were pleased to observe that the Negishi reagent enabled us to convert 1a into 2a as a single E– isomer after hydrolysis in a good isolated yield through the expected allylic C–H bond activation sequence followed by a selective C–C bond cleavage (Scheme 4). Our mechanistic rationalization for the above transformation was that the π– allyl zirconocene hydride species X, resulting from an allylic C–H bond activation reaction of the zirconacyclopropane


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IX, would initiate the isomerization and would generate the new zirconacyclopropane XI after readdition of the metal– hydride species onto the hydrocarbon chain.24 As – metalated cyclopropyl species are known to undergo ring– opening reactions,25 the zirconacyclopropane XI undergoes a selective C1–C3 bond cleavage to form the π–alkyl– allylzirconocene intermediate IIIa (probably in haptotropic equilibrium with its –bonded form IIIb) as described in Scheme 4. The origin of the selectivity for the ring cleavage (C1–C3 versus C1–C2) is kinetically and thermodynamically governed by the formation of the primary carbon zirconium bond (C3–Zr, formation of III) rather than the formation of the tertiary carbon zirconium bond (formation of a C2–Zr bond as represented in VI), although the activation could have potentially occurred at the benzylic position (if one uses 1a,b as starting materials).26 The formation of a discrete bismetalated σ,π–allylzirconocene species IIIa was confirmed by deuterolysis after the isomerization/ring– opening sequence and 2ad2 was obtained with both isotopic incorporation at the primary alkyl (C3) and allylic (C2’) positions. From this experiment, we could already conclude that the zirconocene complex allowed not only an isomerization of the double bond (Zr–walk) but also a selective C1–C3 bond cleavage and site–selective electrophilic substitutions. When the chain length between the cyclopropyl unit and the unsaturation was increased (n = 6 for 1b), comparable yields were obtained (2b) albeit with a slight decrease in yield. Additionally, we could take advantage of the different nucleophilic properties of the resulting bimetallic species (allyl– vs. alkylzirconocene moieties) by discriminating their reactivity towards different electrophiles. Indeed, the allylzirconocene fragment of III, whose reactivity has been well established,27 may selectively react with carbonyl compounds, such as acetone, at the C2’ position in a SE2’ fashion. Even in the presence of an excess of acetone, no trace of compounds resulting from the reaction of alkylzirconocene moiety with ketone at C3 was detected. However, the subsequent addition of I2 allowed the functionalization of the remaining alkylzirconocene segment yielding 2C.

The singularity of this dual reactivity was further exploited (see Schemes 5 and 6). Importantly, exclusively E–alkenes were produced (E/Z > 98:2) through this methodology, independently of the nature of the substituents (R 1), chain– length (n) and electrophiles (E1–X and E2–X) used. Once the sequence of allylic C–H activations and selective C–C bond cleavage was established, the potential of this transforScheme 4. Representative examples of the remote zir- mation to obtain two stereogenic centers in a controlled conocene–induced fragmentation of –ene cyclopro- 1,4–relationship was further investigated (Scheme 5). When diastereomerically pure compound 1d (R1 = Me, R2 = Bu) panes (for the extended scope, see reference 17e). was treated with Cp2ZrC4H8 under similar experimental conditions, derivative 2d was formed as a mixture of two diastereoisomers in a 3:1 ratio (Scheme 5). To rationalize the obtained ratio, we hypothesized that a mixture of trans– and cis–allylzirconocene species might be responsible for this impediment (IIIb-trans and IIIb-cis respectively), both reacting with acetone and consequently leading to the two observed sp3–centered diastereoisomers. To improve this ratio, one solution consisted in isomerizing the Z– configured species IIIb-cis into its more thermodynamically stable E–isomer IIIb-trans prior to the addition of the first electrophile.17e We were pleased to observe that this interconversion was effective by adding THF and heating the reaction mixture at 56 °C for 3 hours, following our pre–set experimental conditions. By introducing this additional event, the transformation of 1d then provided the product



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2d in an excellent 95:5 diastereomeric ratio, highlighting chemical information could be altered. To get insights for the excellent relay of stereochemical information from posi- this thermal isomerization step, DFT(MO6) calculations with implicit SMD solvation (Et2O) were carried out tion C1 to C2’ (Scheme 5). (Scheme 5).17e, 24 To further investigate this thermally induced interconversion (Scheme 5), we are detailing the Scheme 5. 1,4–diastereoselectivity in acyclic products 2 computational studies previously initiated. Thanks to the from –ene cyclopropanes 1 (for the extended scope, reversible isomerizations shown in Figure 1, four zirconosee reference 17e). cene isomers (A–D) are produced in equilibrium via a common zirconocene–allyl–hydride intermediate I. The ring opening events from these four isomers were considered, and this highlights the importance of the syn– vs anti– periplanar relationship required between the cyclopropane methylene unit and the zirconocene. In intermediates C and D, zirconacyclopropane is trans–periplanar to the less substituted cyclopropane C–C bond. Thus, the cyclopropane ring opening requires a large distortion that is kinetically prohibitive (G≠ > 35 kcal mol-1) (Figure 2). In contrast, in intermediates A and B, a syn relationship between these bonds lowers the energy barrier by 30 kcal mol-1, yielding G≠ of 1.5 and 5.4 kcal mol-1 for TSB-IMaj and TSA-Imin, respectively. Complex IMaj, which accounts for the major final diastereoisomer is kinetically favored over Imin. It is also the most stable ring opening activation isomer by 4 kcal mol-1. Hence, TSA-Imin accounts for the formation of the final minor diastereoisomer. To explain the epimerization in favor of IMaj observed upon heating, all plausible routes that connect Imin to IMaj were explored. The most favorable pathway entails the 3–allylic intermediate I and relies on the reversible formation of IMaj from Imin via I using the elementary steps described previously in Figure 2. Since Imin is 8.2 kcal mol-1 lower in energy than the reactants, heating is required to overcome the exoergicity and pass through the transition states and intermediates that link Imin to IMaj. The high diastereoselectivity observed in this transformation results from a dynamic thermodynamic Having in hands this improved protocol, few representative process in which heating increases the stereocontrol of the diastereomerically pure ω–ene–cyclopropanes 1e–f (for full reaction. Remarkably, this stereocontrolled remote funclist of examples, see reference 17e) were successfully treated tionalization results from unselective C–H bond activations with the Negishi reagent Cp2ZrC4H8, then electrophiles, to and reversible cyclopropane ring opening thus enabling the produce the corresponding functionalized acyclic products micro–reversibility of all events until the lowest energy 2e,f, bearing the original quaternary center and newly creminimum is fully reached. ated allylic tertiary stereogenic centers with excellent diastereoselectivities (Scheme 5). In all cases, yields and dia- Figure 2. Dynamic processes stereomeric ratios remained excellent invariably of the chain–length. It should be noted that the reaction is not restricted to substrates with a terminal double bond as internal olefin 1f provided also 2e as a single stereoisomer using our standard conditions. Importantly, the final stereochemical outcome of the double bond seems independent of its initial geometry since both E– and Z–isomers of 1f provide only the E–compound 2e. This last result thus clearly assessed the regioconvergency of the Zr–walk process. Despite these excellent results, we were puzzled to experimentally observe that the thermal conversion of cis IIIb-cis into trans–substituted allylzirconocene IIIb-trans (isomerization at C2’) event proceeded without inducing any scrambling of the stereochemistry at the C1 position. This notable high stereoelectronic control raised the question of its origin since the formation of a single product requires a large number of elementary steps during which stereo-


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Having now a better understanding of the overall sequential Scheme 7. Non diastereoselective reaction of aldehydes process, we decided to further increase the versatility and with allylzirconocene originating from –ene cycloscope of this approach by functionalizing the remaining sp3 propanes 1 carbon–zirconium bond with carbon electrophiles (while fixing E1X as acetone). Although the ionic character of the sp3 C–[Zr] bond is similar to a C–Mg bond, only readily reactive electrophilic reagents such as H3O+ or I2 proved to directly react with the sp3 C–[Zr] bond, presumably owing to the steric shielding of the two cyclopentadienyl ligands. To circumvent the lack of reactivity of this σ–carbon–metal bond, we anticipated that its transmetalation into copper species could solve this issue.28 Scheme 6. Copper(I)–catalyzed subsequent modular functionalization of the remaining sp3 C–[Zr] bond

Following the assessment of all electrophilic substitutions, we then envisaged to selectively cleave 1,1,2,3– tetrasubstituted cyclopropane such as 1h (Scheme 8). If selective, we expected to obtain a secondary sp 3 organozirconocene species XII,29 which in some cases was reported to be configurationally stable30 (Scheme 8). However, all attempts to promote the isomerization / selective C–C bond cleavage sequence of 1h led to a complex reaction mixture. Scheme 8. Attempt to extend the sequence to 1,1,2,3– tetrasubstituted –ene cyclopropane 1h

Gratifyingly, after addition of the first electrophile (acetone), the introduction of a catalytic amount of CuI2LiCl in the reaction mixture allowed to considerably expand the scope of the second functionalization.17e,28 For instance, SN2’–type processes could be carried out with allyl or propargyl bromide to give 2g and 2h respectively. C(sp3)–C(sp2) bonds were directly formed using acyl chlorides (2i and 2j), or indirectly via a Pd–catalyzed cross–coupling reaction with phenyl iodide (2k, Scheme 6). As our strategy led to products bearing stereogenic centers in a highly stereodefined 1,4–relationship, we attempted to add another level of stereochemical complexity by studying the addition of prochiral substrates such as aldehydes or imines as first electrophiles (E1X). Whereas N–(tosyl)benzylideneimine and N–(diphenylphosphinyl)benzaldimine proved to be unreactive towards the intermediate III (described in Scheme 4), the use of aliphatic or aromatic aldehydes with 1d,g led to the linear products 2l–n in good yields but with a disappointing diastereoisomeric ratio (Scheme 7). Extensive efforts to improve this ratio by further tuning the experimental conditions turned out to be fruitless.

2.3. Reactivity of ω–ene–spiro[2.2]pentanes We were then interested to extend our approach to –ene alkenyl spiro[2.2]pentanes 3. These smallest encountered spirocarbocycles31 have a higher ring strain energy (63 kcal mol-1) than two cyclopropanes taken separately (27.5 kcal mol -1) suggesting an even higher propensity towards fragmentation.32 Moreover, unlike thermal, radical, ionic or carbene– induced cleavage of spiro[2.2]pentanes, the transition– metal assisted transformations of these entities usually lead to selective outcomes, therefore potentially becoming of synthetic use. For instance, selective single or double ring opening procedures of spiro[2.2]pentanes were already



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ratios (see Supplementary Material), we then focused on their behavior using our zirconocene–based methodology. When 3a was treated with the Negishi reagent, we were gratified to observe a rapid and clean isomerization reaction followed by a selective single C–C bond cleavage providing after reaction with acetone and subsequent hydrolysis, 4a in 64% yield as a single E–isomer without any trace of second C–C bond cleavage product (Scheme 9). Notably, the stereoselectivity of the conversion of 3a into 4a was high (ds > 98:2), as the isolated mixture 4a (dr 95:5) presented almost the same diastereomeric ratio than its precursor (3a).

reported, although the single–ring opening mode is less encountered. For example, de Meijere initially showed the possibility of inducing a single ring–opening mode through the [Co2(CO)8]–catalyzed carbonylation of vinyl spiro[2.2]pentanes33 and of 4–methylenespiro[2.2]pentanyl methanols.34 In parallel, a double ring–opening of spiro[2.2]pentanes was also reported to be involved in a Heck arylation,35 a Rh(I)–catalyzed carbonylation36 or a Ru(II)– catalyzed full ring–opening followed by a subsequent [4+2] dimerization reaction.37 Following the development of a straightforward access38 to various –ene alkenyl spiro[2.2]pentanes 3 in good to excellent diastereoisomeric

Scheme 9. Combined isomerization–selective mono C–C bond cleavage of –ene alkenyl spiro[2.2]pentanes 3a-e

1) Cp2ZrC4H8, Et2O, -78 to 25 °C, 12 h 2) R3COR3, 0 °C, 2.5 h 3) E2-X, 0 °C, 2.5 h 4) H3O+

n

R1

n-1

R2

R2 3a-d

3

Me Me

4

Me Me

3a dr 95:5

R3

E2

Me

R1 4a-h

5

Me

3b dr 95:5

HO R3

iBu Me

3c dr 95:5

3d dr 65:35:5:0

Mechanistic hypothesis for n = 1 CH3 Cp 2ZrBu2

R1 R2

R1 R2

Allylic C-H bond activation

[Zr] = Cp2Zr

R1

[Zr] XIII

Selective mono C-C bond cleavage

[Zr]

R2

R2

XIV

CH3

R3

R1

R3COR3

[Zr] O

XV

E2-X

R3

E2

R3

R2

HO R3 R1 4

Scope Pr H Me

Pr Me

Me

HO Me

Pr Me

D Me

Me

HO Me

Me

4ad (from 3a) 59% E1-X = MeCOMe E2-X = D3O+ E:Z = > 98:2, ds > 98:2

4a (from 3a) 64% E1-X = MeCOMe E2-X = H3O+ E:Z = > 98:2, ds > 98:2

HO Me

Me

Me

HO Me

4e (from 3b) 77% E1-X = MeCOMe E2-X = AllylBr E:Z = > 98:2, ds > 98:2

Me

Me

Bu Et

D Me

Me

HO Et

Me

HO Me

Me

4f (from 3c) 70% E1-X = MeCOMe E2-X = H3O+ E:Z = > 98:2, ds 90:10

iBu

HO Me

Me

HO Me

4g (from 3d) 82% E1-X = MeCOMe E2-X = H3O+ E:Z = > 98:2, ds 98:2

The presence of the remaining sp3 carbon–zirconium bond enabled the subsequent functionalization by deuterolysis (formation of 4ad) or by an allylation reaction after transmetalation with a catalytic amount (10 mol%) of CuI2LiCl (formation of 4b). This tandem sequence was applied to various –ene alkenyl spiro[2.2]pentanes 3a–d and as previously discussed, longer alkyl chain between the strained ring –namely here the spiro[2.2]pentane unit– and the unsaturation’s relative positioning did not hamper the overall transformation. Yields resulting from the isomerization followed by the selective mono– C–C bond cleavage of 3a, 3b and 3c (with n = 3, 4 and 5 respectively) were indeed comparable. This approach allowed the formation of 1,1,2,2– (E)–vinyltetrasubstituted cyclopropanes motifs seemingly challenging to prepare otherwise via more conventional

Me

4d (from 3b) 62% E1-X = MeCOMe E2-X = H3O+ E:Z = > 98:2, ds > 98:2

4cd (from 3a) 79% E1-X = EtCOEt E2-X = D3O+ E:Z = > 98:2, ds 90:10

Me

H

Me

H

Me Me

H

HO Et

4c (from 3a) 76% E1-X = EtCOEt E2-X = H3O+ E:Z = > 98:2, ds 95:5

Pent Me

Me

Et

H

4b (from 3a) 66% E1-X = MeCOMe E2-X = AllylBr E:Z = > 98:2, ds 95:5

Bu

Me

Me

Pr

Pr Me

Me Me

iBu

HO Me

4h (from 3d) 79% E1-X = MeCOMe E2-X = AllylBr E:Z = > 98:2, ds > 98:2

strategies. As previously observed with alkenyl cyclopropanes (see Scheme 7), the addition of aldehyde such as isobutyraldehyde also proceeded smoothly, although without any diastereocontrol (stereochemistry at the carbinol center is not controlled as already depicted in Scheme 7, compound not reported in Scheme 9). Following the development of this straightforward approach for a selective mono– C–C bond cleavage, we then turned our attention to promote the second C–C bond cleavage to provide potentially the diene (5). All our attempts to directly cleave the two rings of the spiro[2.2]pentane failed as the ––zirconocene complex XIV resulting from the first scission did not induce the desired second ring–cleavage, most probably due to rotational constraints. We presumed that a suitable solution would be to disengage the zirconocene complex from its –


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system after addition of the first electrophile. The gained flexibility should then allow rotations over the C–Zr bond, required to optimally perform the second C–C bond cleavage. We initially observed that the reaction led to the expected second ring–cleavage product 5a, albeit in very low yield, when the complete sequence of isomerization – first C–C bond fragmentation and reaction with acetone were performed in THF (Table 1, entries 1 and 2). This result underlined that a more polar solvent might be required to weaken the presumed aggregate described in XV and induce the second ring fragmentation. However, THF was clearly not an appropriate solvent for the zirconium–walk reaction (Table 1, entry 2) and Et2O was used as solvent for all subsequent studies. We then further screened the influence of various parameters to promote the second ring–opening of the intermediate XV (Table 1). Adding THF or 2-MeTHF as cosolvent after the first ring–opening and heating the reaction mixture slightly increased the ratio in favor of the double–opening product (Table 1, entries 3 and 4). To further weaken the O–[Zr] bond, we then opted for additives to transmetalate the C–[Zr] bond. Addition of a Lewis base, such as MeLi, in the reaction mixture to produce an expectedly more reactive “organozirconate” complex (Table 1, entry 5) or adding Zn(II) salts to promote a transmetalation into an alkylzinc species (Table 1, entry 6) did not significantly lead to the desired second cyclopropane ring–opening reaction. Only the addition of a Lewis acid such as TMSCl at room temperature proved to be beneficial (Table 1, entry 7). Heating the reaction mixture to reflux over 12 hours led to a complete full ring–opening of the initial spiro[2.2]pentane substrate (Table 1, entry 8). Whereas TMSOTf induced the elimination of the alcohol moiety in 5a (Table 1, entry 9), BF3OEt2 was eventually found to be the most efficient Lewis acid affording the desired 4,6–diene 5a in satisfactory yields and with still an excellent E–selectivity (Table 1, entries 10 and 11).

Various –ene spiro[2.2]pentanes 3a,b,d were then subjected to these optimized conditions (Scheme 10). As previously mentioned, the reaction proceeded invariably of the chain length (n = 1 to 4) affording adducts 5 after reaction with a ketone followed by hydrolysis with excellent E/Z ratios. Therefore, through the development of these two protocols (see Schemes 9 and 10), spiro[2.2]pentane motifs could modularly and selectively undergo either one or two ring– opening events to respectively yield vinyl cyclopropanes (4) or 1,3-dienes structure valuable for further reactions (5).

Table 1. Screening of experimental conditions for the induction of the second ring–opening mode converting Scheme 10. Scope of the remote and selective double ring–opening of ω– ene spiro[2.2]pentane ω–ene spiro[2.2]pentane 3a into diene 5a.



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duce the isomerization of the double bond to release the strain. The resulting zirconacyclopropane would then undergo a selective C1–C3 bond cleavage (Scheme 12) to give the previously mentioned intermediate III (Scheme 1) for the transformation of –ene cyclopropanes 1 into acyclic fragments 2. To further probe our mechanistic understanding, we used the allylic CD3–labelled 8e as starting ACP and the product resulting from this combined allylic C–H bond activation and C–C bond cleavage gave 2s in excellent yield possessing two deuterium atoms at the allylic and one deuterium atom at the vinylic positions supporting our mechanistic hypothesis. In all cases, the combined allylic C–H bond activation followed by the selective C1–C3 bond cleavage proceeded smoothly to afford a large variety of linear products 2o–2q in excellent yields. As enantiomerically enriched ACPs are easily accessible41 and because the quaternary carbon stereocenter is at no risk of epimerization during the process, the optical purity of 2r was assumed to be identical from its ACP precursor 8d. When enantiomerically enriched 8d (er 98:2)41c-e was treated under our experimental conditions, the acyclic product 2r possessing the quaternary carbon stereocenter was indeed obtained in excellent yields as unique E–isomer. The enantiomeric ratio of (2E,4R)–4– ethyl–4–methyl–octene 2r was determined by correlation with an authentic sample.46 As expected, 2r was obtained with the same enantiomeric ratio (er 98:2) than the starting material 8d confirming that the overall reaction proceeds without altering the stereochemistry of the quaternary carbon stereocenter. By a hydrogenation reaction of the double bond of 2r, the simplest crypto–optically active saturated Scheme 11. Remote and selective cleavage of C–C and hydrocarbon 10 with a quaternary carbon stereocenter was C–O bonds in cyclopropyl carbinol methyl ethers. Rep- successfully prepared.47 Our strategy appears to be an apresentative examples are described. For the full list, pealing alternative to those previously reported in this resee reference 17g gard.47

2.4. Reactivity of ω–ene–cyclopropanes possessing a leaving group. Similar isomerization/carbocycle fragmentation sequence could also be applied to –ene cyclopropane possessing a strategically positioned leaving group (in this case, a methoxy moiety), by taking advantage of the zirconocene inherent strong oxophilicity. When diastereopure cyclopropyl methyl ethers 6, also potentially obtained enantiomerically enriched,15 were treated with the Negishi reagent, a sequence of isomerization followed by a C–C bond fragmentation39 as depicted in XVII gave the corresponding allylzirconocene species and after acetolysis, the dienes 7 with an excellent E:Z ratio as described in Scheme 11. Owing to the potential steric repulsions between the Cp groups of the zirconocene and the quaternary stereocenter, we hypothesized that the allylzirconocene XVIII should be the predominant isomer among all the possible haptotropic forms. Surprisingly, only acetolysis provided a good selectivity for the protonation reaction at the–position as addition of H3O+ gave a mixture of  and –isomers. A concerted allylic protonation as depicted in Scheme 11 could potentially explain the positional selectivity of the olefin. Several – ene cyclopropyl carbinol methyl ethers 6 were subjected to these conditions and in all cases unconjugated dienes 7a–d were obtained with excellent positional selectivity of the internal double bond.17g This reaction was not restricted to short alkenyl chain (n = 1) as longer alkyl chain (n= 3) also successfully led to the unconjugated diene 7d in a good yield although with a slightly lower E/Z ratio.

Scheme 12. Isomerization followed by C–C bond cleavage of ACPs. Representative examples are described. For the full list, see reference 17g

2.5. Reactivity of alkylidenecyclopropanes. We also extended this strategy to a different family of small strained ring derivatives, namely alkylidenecyclopropane (ACPs) species.40,41 These substrates should be excellent candidates for this transformation as we have already reported the metal–catalyzed hydroboration,42 hydrostannylation,43 hydrosilylation44 and hydroformylation45 reactions with selective ring–opening of the cyclopropyl ring. Based on the high reactivity of the exoalkylidene moiety of ACPs,44 we reckoned that the Negishi zirconocene species should first in-


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The Journal of Organic Chemistry originate from a backward chain–walking process. However, this hypothesis was also not supported by the calculations as no difference was found between the two substrates. Although it could not be fully computationally confirmed due to the very large conformational space to consider for a large number of isomers of similar energies involved in the various isomerisations, the phenyl moiety most likely prevented (or enabled) specific rotations to occur, allowing the metal center to switch from one diastereotopic face to another.48 Scheme 13. Diastereoselective reaction with ACPs

Finally, we were interested to use ACPs to create a new and distant stereogenic center (1,4–relationship from the initial quaternary carbon stereocenter). When ACP 8a, possessing two different alkyl groups at the quaternary stereocenter, was treated in our experimental conditions, the product 2t was obtained in excellent yield as a single E–isomer but as two diastereoisomers in a 1:1 ratio (Scheme 13, path a). Nonetheless, for substrates possessing a phenyl moiety at the quaternary center of the alkylidenecyclopropane (Scheme 13, path b), the reaction led to an excellent diastereoselectivity as 2u was obtained in an excellent diastereoisomeric ratio of above 98:2 (77% yield). Several acyclic products 2v–2x were also remarkably produced with similar excellent selectivities. The dramatic effect of the presence of this phenyl moiety was computationally investigated. Considering the minimum steric difference between the two alkyl groups (Me and Et) of 8a, one could hypothesized that the two faces of the ACP were equally accessible for reaction with the zirconocene complex while one of the two faces of 8c was preferred when an aryl group was present. However, this hypothesis was not supported by the DFT calculations as the coordination of the two faces with the zirconocene reagent for 8a as well as for 8b was found to be energetically equivalent with ΔΔrG° ≤ 0.8 kcal mol-1. As the coordination essentially proceeds equally on the two faces, we then imagined that the lowest energy pathway could

3. CONCLUSION In summary, several approaches using organozirconocene species for the remote cleavage of strained three–membered ring carbocycles such as –ene polysubstituted cyclopropanes, alkylidenecyclopropanes, –ene spiro[2.2]pentanes and –ene cyclopropyl methyl ethers, into stereodefined organometallic intermediates were successfully developed to access highly stereoenriched acyclic scaffolds in good yields. All of these protocols formally enable the C–C or/and C–O bonds activation distant from the original olefin through a cascade of well–controlled chemical events.49 These resulting acyclic products including stereocenters were readily obtained with excellent selectivities in most cases. DFT calculations and isotopic labeling were performed to delineate the nature of the organometallic intermediates and the origin of the stereoselectivities. Remarkably, the large number of fast and reversible isomerizations involved in these transformations contribute to a highly stereoselective reaction which is in turn under thermodynamic control. This was shown to be in the –ene cyclopropane and also suggested for the alkylidenecyclopropanes. By showing the extended scope and limitations of these zirconocene–based transformations, we hope to further illustrate the power of such cascade reactions, prospectively useful for the elaboration of complex hydrocarbon acyclic scaffolds. Efforts to develop similar conceptual synthetic strategies in a catalytic



fashion are currently being carried out in our laboratory. Most importantly, through this work, we hope to inspire other synthetic chemists to grasp all the potential of implementing remote disconnections in their retrosynthetic planning.

EXPERIMENTAL SECTION General comments All reactions were carried out under an atmosphere of argon, with flame-dried flasks under positive pressure of argon and with dry, oxygen-free solvents using standard Schlenk techniques. All organometallic compounds, dry solvents and other air or moisture sensitive reagents were transferred using plastic single-use graduated syringes and oven-dried stainless steel needles. Progress of the reactions was monitored by analytical TLC using glass plates precoated with silica gel with F254 indicator (Merck). Visualization of spots was done using phosphomolybdic acid, p-anisaldehyde or potassium permanganate stains followed by heating. Frontal ratios (Rf) of synthesized compounds were determined from the reaction crude by analytical TLC using glass plates precoated with silica gel with F254 indicator (Merck). Purification of crude mixtures was accomplished by column chromatography on silica gel 60 Å (GraceResolv) using gradients mixture n-pentane / diethyl ether, n-hexane / diethyl ether or pure pentane or hexane. H and 13C NMR spectra were measured on Brucker Avance AV200 (200 MHz 1H, 50 MHz 13C), Brucker Avance AV300 (300 MHz 1H, 75 MHz 13C), Brucker Avance AV400 (400 MHz 1H, 101 MHz 13C) spectrometer in CDCl3 and referenced to TMS. Chemical shifts values (δ) are reported in ppm (calibration of spectra to the residual peak of CDCl3: δ = 7.26 ppm (s) for 1H NMR; δ = 77.16 ± 0.06 ppm for 13C NMR). All the proton spectra reported as following: δ value (multiplicity, J coupling constant in Hz, number of nuclei). Multiplicity contractions used: (bs) – broad singlet, (d) – doublet, (dd) – doublet of doublet, (ddd) – doublet of doublets of doublets, (ddt) - doublet of doublet of triplets, (dddt) – doublet of doublets of doublets of triplets, (dt) – doublet of triplets, (m) – multiplet, (t) – triplet, (td) – triplet of doublets, (tq) – triplet of quartets, (tt) – triplet of triplets, (q) – quartet, (s) – singlet, (p) – quintuplet. E/Z and diastereomeric ratios were evaluated by 1H and 13C NMR analysis respectively. 1

Electrospray ionization mass spectrometry analyses were obtained on a APCI instrument by Maxis Impact (Bruker) and on a LCT Premier (Waters). Solvents and reagents THF and diethyl ether (HPLC grade, non-stabilized, BioLab) were dried using Innovative Technology PureSolv PS-MD-2 solvent purifier (aluminum oxide columns) and kept under positive pressure of nitrogen (99.9999% purity grade). Bis(cyclopentadienyl)zirconium(IV) dichloride, copper(I) iodide, copper(I) chloride and copper(I) bromide dimethyl sulfide complex were purchased from ACROS, Aldrich or Alfa Aesar and used as received. n-Butyllithium solution in hexanes (1.6 M) was commercially obtained from Aldrich and regularly titrated under argon atmosphere by 1 M solution of 2-isobutanol in toluene, using 1,10-phenantroline as

Page 12 of 23

indicator. All organomagnesium reagent solutions in diethyl ether were homemade and prepared according to standard procedures, except for methylmagnesium bromide solution (3 M in diethyl ether) which was purchased from Aldrich. Grignard solutions were regularly titrated under argon atmosphere by 1 M solution of 2-isobutanol in toluene, using 2,2’-biquinoline as indicator. All the reagents used for the preparation of starting materials were purchased from commercial suppliers and used without further purification except for oxalyl chloride which was distilled prior to use. Ketone and aldehyde compounds, allyl bromide, benzoyl chloride and iodobenzene were purchased from commercial suppliers and distilled prior to use under an atmosphere of argon as follows: acetone was distilled from CaSO4, diethyl ketone was distilled from P2O5, cyclohexanone, cyclopentanone were distilled from MgSO4, allyl bromide, benzoyl chloride, benzaldehyde, mesitaldehyde and iodobenzene were distilled from CaCl2. Propargyl bromide solution (80 wt.% in toluene), 4-methylcyclohexanone, 4-tertbutylcyclohexanone, N-(diphenylphosphinyl)benzaldimine were commercially obtained and used as received. Starting materials and products ω-ene cyclopropanes 1a-h were prepared using previously reported procedures.15n,17c,17e,17g ω-ene cyclopropyl methyl ethers 6 were synthesized from their corresponding already well-charaterized ω-ene cyclopropyl carbinol derivatives17a through a standard nucleophilic substitution using NaH and iodomethane. Alkylidenecyclopropanes 8a-d were obtained according to a synthetic route previously reported. 17c,17f,17j All analytic data of the compounds 2a-c17g 2d-n,17e 2o-x17g and 7a-d17g, 1017g can be found in the literature. Preparation of starting materials 3a-d General procedure for the synthesis of homoallenyl alcohols IIa-c Homoallenyl alcohols IIa,b were prepared from the corresponding commercially available propargyl alcohols Ia,b using a previously reported procedure. 50 General procedure for the synthesis of 2-(spiro[2.2]pentan-1yl)ethanols IIIa,b Into a flame-dried three-neck flask, equipped with a stir bar, a low temperature thermometer, a rubber septum and an inert gas inlet, a diethyl zinc solution 1.0 M in hexanes (4 equiv.) was added to anhydrous DCM (5 mL for 1 mmol of II) at 0 °C under argon atmosphere and the resulting mixture was stirred for 5 min at this temperature. Freshly distilled trifluoroacetic acid (TFA) was thereafter added dropwise (CAREFUL: exothermic and gas production) at that temperature and the mixture was stirred at 0 °C for 30 min. Diiodomethane (4 equiv.) was then added dropwise to the reaction mixture while maintaining the internal temperature at 0 °C. After completion of the addition, the resulting solution was stirred for an additional 30 min period at 0 °C. A dry DCM solution of the homoallenyl alcohol II (1 equiv., 1 mL for 1 mmol of II) was then added via syringe while maintaining the internal temperature under 0° C at all time. The reaction mixture was allowed to warm-up slowly to room temperature and was stirred for 12 h under an inert atmosphere. After completion of the reaction mixture, the reac-


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at 0 °C and the resulting mixture was further stirred for another 2 h period. The reaction was lastly quenched with a 0.1 M-HCl solution. The layers were separated and the aqueous layer was extracted with Et2O (twice). The combined organic fractions were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The product IVb was purified by silica-gel chromatography Typical procedure for the synthesis of IVa (SiO2, or n-hexane / Et2O, 70:30) and directly engaged into Into a flame-dried 250-mL three-neck flask, equipped with a the next reaction. stir bar, a low temperature thermometer, a rubber septum and an inert gas inlet, dry DMSO (2.1 mL, 30.1 mmol), dilut- General procedure for the synthesis of 3a, 3b and 3c tion was quenched with a 1 M HCl solution. The layers were separated and the aqueous phase was extracted with DCM (three times). The combined organic fractions were dried over MgSO4, filtered and concentrated under reduced pressure. The products IIIa,b were isolated by silica-gel chromatography (SiO2, n-hexane / EtOAc, 90:10).

ed in dry DCM (5 mL), was added to a dry DCM solution (150 mL) of oxalyl chloride (1.9 mL, 22.5 mmol) at – 78 °C under an inert atmosphere. After a 10-min stirring period at -78 °C, a dry DCM solution (7 mL) of alcohol IIIa (2.770 g, 15.03 mmol) was added dropwise while maintaining the stirred reaction mixture at -78 °C. After 15-min stirring period at 78 °C, freshly distilled Et3N (11.53 mL, 82.67 mmol) was added dropwise and the reaction mixture was stirred at -78 °C for an additional 30-min period and then warmed-up to room temperature for 6 h. The reaction was lastly quenched with a saturated aqueous NaHCO3 solution. The layers were separated and the aqueous phase was extracted with Et 2O (twice). The combined organic fractions were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by silica-gel chromatography (SiO2, n-hexane / Et2O, 90:10) to afford IVa, which was rapidly engaged into the next reaction (decomposition over time).

A flame-dried three-neck flask equipped with a stir bar, a low temperature thermometer, a rubber septum and an inert gas inlet was charged with CuBr.DMS (0.1 equiv.) and a dry Et2O solution (10 mL for 1 mmol of substrate) of the mesylate compound IVb or IVc (1.0 equiv.). The reaction mixture was allowed to stir for 10 min at 0 °C (ice bath) under an inert atmosphere. An Et2O solution of alkenylmagnesium bromide (2 equiv.) was then added dropwise at 0 °C and the resulting black solution was stirred at room temperature for 2 h under an inert atmosphere. After completion of the reaction, it was quenched with a saturated aqueous NH4Cl solution at 0 °C. The layers were separated and the aqueous phase was extracted with Et2O (twice). The combined organic fractions were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure (CAUTION: the compounds are volatile). The products 3a, 3b, 3c were isolated by silica-gel chromatography (SiO2, npentane, 100%).

Typical procedure for the synthesis of 3d Into a flame-dried 250-mL three-neck flask, equipped with a stir bar, a low temperature thermometer, a rubber septum and an inert gas inlet, a dry THF solution of t-BuOK (2.657 g, 23.68 mmol) was added to a Ph3PMeBr (8.459 g, 23.68 mmol) suspension in dry THF (240 mL) at -20 °C under an inert atmosphere. After 2 h-stirring period at a temperature between -20 and -5 °C, a dry THF solution of aldehydic compound IVa (2.158 g, 11.84 mmol) was added dropwise at 5 °C. The reaction mixture was allowed to warm-up to room temperature and after 12 h, the reaction was quenched with a saturated aqueous NaHCO3 solution. The layers were separated and the aqueous phase was extracted with Et2O (twice). The combined organic fractions were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure (CAUTION: the compound is volatile). The crude was purified by silica-gel chromatography (SiO 2, n-pentane, 100%) to afford 3d as a colorless oil (1.309 g, 62%). General procedure for the synthesis of IVb A flame-dried three-neck flask equipped with a stir bar, a low temperature thermometer, a rubber septum and an inert gas inlet was charged with 4-(dimethylamino)pyridine (0.25 equiv.) and a dry DCM (10 mL for 1 mmol of III) solution of the spiropentane alcohol IIIb (1.0 equiv.). The reaction mixture was allowed to stir for 15 min at 0 °C (ice bath) under an inert atmosphere. Freshly distilled Et3N (2 equiv.) was then added dropwise to the reaction mixture at 0 °C and the resulting solution was stirred for 10 min at 0 °C. Methanesulfonyl chloride (2.5 equiv.) was then added dropwise

General procedure for the synthesis of 2 from ω-enecyclopropanes 1 General procedure for the synthesis of 2a-b from 1a-b A flame-dried 50-mL three-neck flask equipped with a stir bar, a low temperature thermometer, a rubber septum and an inert gas inlet was charged with bis(cyclopentadienyl)zirconium dichloride (292.0 mg, 1.0 mmol) and dry Et2O (10 mL) under an inert atmosphere. After cooling down the stirred reaction suspension to -78 °C, a solution of n-butyllithium (1.6 M in hexanes, 1.25 mL, 2.0 mmol) was added dropwise at that temperature. After stirring for 1 hour at -78 °C, a 2 mL dry Et 2O solution of substrate 1a-b (0.5 mmol) was added dropwise to the solution at -78 °C and the resulting mixture was allowed to slowly warm-up to room temperature overnight (12 h) at which time the reaction mixture was a yellow-orange suspension. An aqueous solution of 1M HCl (or DCl) was then added and the phases were separated. The aqueous phase was extracted with Et2O (5 times). The combined organic fractions were washed with an aqueous saturated NaHCO3 solution and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The products 2a-b were isolated by silicagel chromatography (SiO2, n-pentane or n-hexane, 100%). Typical procedure for the synthesis of 2c from 1c A flame-dried 50-mL three-neck flask equipped with a stir bar, a low temperature thermometer, a rubber septum and an inert gas inlet was charged with bis(cyclopentadienyl)zirconium dichloride (292.0 mg, 1.0



Page 14 of 23

mmol) and dry Et2O (10 mL) under an inert atmosphere. After cooling down the stirred reaction suspension to -78 °C, a solution of n-butyllithium (1.6 M in hexanes, 1.25 mL, 2.0 mmol) was added dropwise at that temperature. After stirring for 1 hour at -78 °C, a 2 mL dry Et 2O solution of substrate 1h (97.2 mg, 0.5 mmol) was added dropwise to the solution at -78 °C and the resulting mixture was allowed to slowly warm-up to room temperature overnight (12 h). The first electrophile, freshly distilled acetone (57 µL, 1.25 mmol) was added dropwise after cooling down the reaction mixture to -30 °C and the resulting solution was allowed to stir for 1 hour at that temperature. The second electrophile, iodine (634.5 mg, 2.5 mmol) in dry Et2O (5 mL) was then added at 0 °C and the reaction mixture was stirred for additional 1 hour at that temperature. Finally, the reaction mixture was hydrolyzed with an aqueous solution of 1M HCl. The layers were separated and the aqueous phase was extracted with Et2O (5 times). The combined organic fractions were washed with a saturated aqueous solution of Na2S2O3, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by silica-gel chromatography using gradient mixtures of ethyl acetate and n-hexane as eluents afforded 2c as a colorless oil (101 mg, 53% yield).

an inert gas inlet was charged with bis(cyclopentadienyl)zirconium dichloride (496.9 mg, 1.7 mmol) and dry Et2O (10 mL) under an inert atmosphere. After cooling down the stirred reaction suspension to -78 °C, a solution of n-butyllithium (1.6 M in hexanes, 2.13 ml, 3.4 mmol) was added dropwise at that temperature. After stirring for 45 min at -78 °C, a 2 mL dry Et2O solution of 1e-f (1 mmol) was added dropwise to the solution at -78 °C and the resulting mixture was allowed to slowly warm-up to room temperature over 5.5 12 hours at which time the reaction mixture was a yellow-orange suspension. Dry THF (40 mL) was then added to the reaction mixture and the resulting solution was heated at 55 °C for 3 hours. The freshly distilled first electrophile (3.0 mmol) was added dropwise after cooling down the reaction mixture to 0 °C and the resulting solution was allowed to stir for 2 hours at that temperature. Finally, the reaction mixture was hydrolyzed with an aqueous solution of 1M HCl. The layers were separated and the aqueous phase was extracted with Et2O (3 times). The combined organic fractions were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. Products 2e-f were isolated by silica-gel chromatography (SiO2, n-pentane / Et2O, 80:20 – 90:10).

Typical procedure for the synthesis of 2d from 1d

Typical procedure for the synthesis of 2g from 1g

A flame-dried 100-mL three-neck flask equipped with a stir bar, a low temperature thermometer, a rubber septum and an inert gas inlet was charged with bis(cyclopentadienyl)zirconium dichloride (496.9 mg, 1.7 mmol) and dry Et2O (10 mL) under an inert atmosphere. After cooling down the stirred reaction suspension to -78 °C, a solution of n-butyllithium (1.6 M in hexanes, 2.13 ml, 3.4 mmol) was added dropwise at that temperature. After stirring for 45 min at -78 °C, a 2 mL dry Et2O solution of substrate 1d (180.4, 1 mmol) was added dropwise to the solution at -78 °C and the resulting mixture was allowed to slowly warm-up to room temperature (over 5.5 hours if n = 1 and 12 hours if n = 3) at which time the reaction mixture was a yellow-orange suspension. Dry THF (40 mL) was then added to the reaction mixture and the resulting solution was heated at 55 °C for 3 hours. Freshly distilled acetone (220 µL, 3.0 mmol) was added dropwise after cooling the reaction mixture to 0 °C and the resulting solution was allowed to stir for 2 hours at that temperature. The second electrophile, iodine (1.269 g, 5.0 mmol) in dry THF (5 mL) was then added at 0 °C and the resulting mixture was stirred for additional 2 hours at that temperature. Finally, the reaction mixture was hydrolyzed with an aqueous solution of 1M HCl. The layers were separated and the aqueous phase was extracted with Et2O (3 times). The combined organic fractions were washed with a saturated aqueous solution of Na2S2O3, brine, dried over MgSO4, filtered and concentrated under reduced pressure. Purification by silica-gel chromatography (SiO 2, npentane / Et2O, 90:10) afforded 2d as a yellow oil (208 mg, 57%).

A flame-dried 100-mL three-neck flask equipped with a stir bar, a low temperature thermometer, a rubber septum and an inert gas inlet was charged with bis(cyclopentadienyl)zirconium dichloride (496.9 mg, 1.7 mmol) and dry Et2O (10 mL) under an inert atmosphere. After cooling down the stirred reaction suspension to -78 °C, a solution of n-butyllithium (1.6 M in hexanes, 2.13 ml, 3.4 mmol) was added dropwise at that temperature. After stirring for 45 min at -78 °C, a 2 mL dry Et2O solution of 1g (180.3 mg, 1 mmol) was added dropwise to the solution at 78 °C and the resulting mixture was allowed to slowly warmup to room temperature over 5.5 hours at which time the reaction mixture is a yellow-orange suspension. Dry THF (40 mL) was then added to the reaction mixture and the resulting solution was heated at 55 °C for 3 hours. Freshly distilled acetone (220 µL, 3.0 mmol) was added dropwise after cooling down the reaction mixture to 0 °C and the resulting solution was allowed to stir for 2 hours at that temperature. The second electrophile, freshly distilled allyl bromide (5.0 mmol, 433 µL), was added to the solution to 0 °C, followed by the addition at that temperature of a dry THF solution (3 mL) of CuI (19.1 mg, 0.1 mmol) and flamedried LiCl (8.5 mg, 0.2 mmol). The resulting mixture was allowed to stir at 55 °C for 2 hours at which time it was quenched with an aqueous solution of 1M HCl. The layers were separated and the aqueous phase was extracted with Et2O (3 times). The combined organic fractions were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by silica-gel chromatography (SiO2, n-pentane / Et2O, 80:20) to afford 2g as a light yellow oil (157 mg, 56% yield).

General procedure for the synthesis of 2e-f from 1e-f

Typical procedure for the synthesis of 2h from 1d

A flame-dried 100-mL three-neck flask equipped with a stir A flame-dried 100-mL three-neck flask equipped with a stir bar, a low temperature thermometer, a rubber septum and bar, a low temperature thermometer, a rubber septum and


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an inert gas inlet was charged with bis(cyclopentadienyl)zirconium dichloride (447.3 mg, 1.53 mmol) and dry Et2O (10 mL) under an inert atmosphere. After cooling down the stirred reaction suspension to -78 °C, a solution of n-butyllithium (1.6 M in hexanes, 1.91 ml, 3.06 mmol) was added dropwise at that temperature. After stirring for 45 min at -78 °C, a 2 mL dry Et2O solution of 1d (153.3 mg, 0.85 mmol) was added dropwise to the solution at -78 °C and the resulting mixture was allowed to slowly warm-up to room temperature over 12 hours at which time the reaction mixture was a yellow-orange suspension. Dry THF (40 mL) was then added to the reaction mixture and the resulting solution was heated at 55 °C for 3 hours. Freshly distilled acetone (315 µL, 4.25 mmol) was added dropwise after cooling down the reaction mixture to 0 °C and the resulting solution was allowed to stir for 2 hours at that temperature. The second electrophile, propargyl bromide (80wt% in toluene, 0.48 mL, 4.25 mmol) was added to the solution at 0 °C, followed by the addition at that temperature of a dry THF solution (3 mL) of CuI (16.2 mg, 0.085 mmol) and flame-dried LiCl (7.2 mg, 0.17 mmol). The resulting mixture was allowed to stir at 55 °C for 3 hours at which time it was quenched with an aqueous solution of 1M HCl. The layers were separated and the aqueous phase was extracted with Et2O (3 times). The combined organic fractions were washed with brine, dried over MgSO 4, filtered and concentrated under reduced pressure. The crude was purified by silica-gel chromatography (SiO2, n-pentane / Et2O, 80:20) to afford 2h as a yellow oil (126 mg, 53%). General procedure for the synthesis of 2i –j from 1g A flame-dried 100-mL three-neck flask equipped with a stir bar, a low temperature thermometer, a rubber septum and an inert gas inlet was charged with bis(cyclopentadienyl)zirconium dichloride (496.9 mg, 1.7 mmol) and dry Et2O (10 mL) under an inert atmosphere. After cooling down the stirred reaction suspension to -78 °C, a solution of n-butyllithium (1.6 M in hexanes, 2.13 ml, 3.4 mmol) was added dropwise at that temperature. After stirring for 45 min at -78 °C, a 2 mL dry Et2O solution of 1g (180.3 mg, 1 mmol) was added dropwise to the solution at 78 °C and the resulting mixture was allowed to slowly warmup to room temperature over 5.5 hours at which time the reaction mixture is a yellow-orange suspension. Dry THF (40 mL) was then added to the reaction mixture and the resulting solution was heated at 55 °C for 3 hours. Freshly distilled acetone (220 µL, 3.0 mmol) was added dropwise after cooling down the reaction mixture to 0 °C and the resulting solution was allowed to stir for 2 hours at that temperature. A dry THF solution (3 mL) of CuI (19.1 mg, 0.1 mmol) and flame-dried LiCl (8.5 mg, 0.2 mmol) was then added at 0 °C, followed by the addition of the corresponding acid chloride (2.0 mmol) at that temperature. The resulting mixture was allowed to stir at 55 °C for 3 hours at which time it was quenched with an aqueous solution of 1M HCl. The layers were separated and the aqueous phase was extracted with Et2O (3 times). The combined organic fractions were washed with brine, dried over MgSO 4, filtered and concentrated under reduced pressure. The crude was puri-

fied by silica-gel chromatography (SiO2, n-pentane / Et2O, 80:20-60:40). Typical procedure for the synthesis of 2i from 1g A flame-dried 100-mL three-neck flask equipped with a stir bar, a low temperature thermometer, a rubber septum and an inert gas inlet was charged with bis(cyclopentadienyl)zirconium dichloride (496.9 mg, 1.7 mmol) and dry Et2O (10 mL) under an inert atmosphere. After cooling down the stirred reaction suspension to -78 °C, a solution of n-butyllithium (1.6 M in hexanes, 2.13 ml, 3.4 mmol) was added dropwise at that temperature. After stirring for 45 min at -78 °C, a 2 mL dry Et2O solution of 1g (180.3 mg, 1 mmol) was added dropwise to the solution at 78 °C and the resulting mixture was allowed to slowly warmup to room temperature over 5.5 hours at which time the reaction mixture is a yellow-orange suspension. Dry THF (40 mL) was then added to the reaction mixture and the resulting solution was heated at 55 °C for 3 hours. Freshly distilled acetone (220 µL, 3.0 mmol) was added dropwise after cooling down the reaction mixture to 0 °C and the resulting solution was allowed to stir for 2 hours at that temperature. A dry THF solution (3 mL) of CuI (19,1 mg, 0.1 mmol) and flame-dried LiCl (8.5 mg, 0.2 mmol) was then added, followed by the addition of iodobenzene (1.1 mmol, 123 µL) and Pd(PPh3)4 (115.5 mg, 0.1 mmol) solubilzed in dry THF respectively at that temperature. The resulting mixture was allowed to stir at 58 °C for 3.5 hours at which time it was quenched with an aqueous solution of 1M HCl. The layers were separated and the aqueous phase was extracted with Et2O (3 times). The combined organic fractions were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by silica-gel chromatography (SiO2, n-pentane / Et2O, 80:20) to afford 2i as an orange oil (158 mg, 50%). Typical procedure for the synthesis of 2l from 1g A flame-dried 100-mL three-neck flask equipped with a stir bar, a low temperature thermometer, a rubber septum and an inert gas inlet was charged with bis(cyclopentadienyl)zirconium dichloride (496.9 mg, 1.7 mmol) and dry Et2O (10 mL) under an inert atmosphere. After cooling down the stirred reaction suspension to -78 °C, a solution of n-butyllithium (1.6 M in hexanes, 2.13 ml, 3.4 mmol) was added dropwise at that temperature. After stirring for 45 min at -78 °C, a 2 mL dry Et2O solution of 1g (180.3 mg, 1 mmol) was added dropwise to the solution at 78 °C and the resulting mixture was allowed to slowly warmup to room temperature over 5.5 hours at which time the reaction mixture is a yellow-orange suspension. Dry THF (40 mL) was then added to the reaction mixture and the resulting solution was heated at 55 °C for 3 hours. Freshly distilled propionaldehyde (215.1 µL, 3 mmol), used as first electrophile, was added at -50 °C and the mixture was allowed to stir for 2 h at that temperature. The reaction mixture was quenched with an aqueous solution of 1M HCl. The layers were separated and the aqueous phase was extracted with Et2O (3 times). The combined organic fractions were washed with a saturated aqueous solution of Na 2S2O3, brine, dried over MgSO4, filtered and concentrated under reduced



Page 16 of 23

pressure. The crude was purified by silica-gel chromatog- A flame-dried 100-mL three-neck flask equipped with a stir raphy (SiO2, n-pentane / Et2O, 90:10) to afford 2l as two bar, a low temperature thermometer, a rubber septum and an inert gas inlet was charged with separated diastereomers (121 mg, 50%). General procedure for the study of the influence of the alde- bis(cyclopentadienyl)zirconium dichloride (496.5 mg, 1.7 mmol) and dry Et2O (45 mL) under an inert atmosphere. hyde on the dr After cooling down the stirred reaction suspension to -78 °C, A flame-dried 100-mL three-neck flask equipped with a stir a solution of n-butyllithium (1.40 M in hexane, 2.4 mL, 3.4 bar, a low temperature thermometer, a rubber septum and mmol) was added dropwise at that temperature. After stiran inert gas inlet was charged with ring for 1 hour at -78 °C, a 5 mL dry Et2O solution of the bis(cyclopentadienyl)zirconium dichloride (496.9 mg, 1.7 substrate 8c (172.3 mg, 1.0 mmol) was added dropwise to the mmol) and dry Et2O (10 mL) under an inert atmosphere. solution at -78 °C and the resulting mixture was allowed to After cooling down the stirred reaction suspension to -78 °C, slowly warm-up to 10 °C overnight (13 h). Freshly distilled a solution of n-butyllithium (1.6 M in hexanes, 2.13 ml, 3.4 acetone (184 µL, 2.5 mmol), serving as first electrophile was mmol) was added dropwise at that temperature. After stiradded dropwise at 0 °C and the resulting solution was alring for 45 min at -78 °C, a 2 mL dry Et2O solution of 1d lowed to stir for 6 hours at that temperature. The second (180.3 mg, 1 mmol) was added dropwise to the solution at electrophile, iodine (1.02 g, 4.0 mmol) was then added at 10 78 °C and the resulting mixture was allowed to slowly warm°C and stirred for additional 3 hours at that temperature. up to room temperature over 12 h hours at which time the Finally, the reaction mixture was quenched at 0 °C with an reaction mixture is a yellow-orange suspension. Dry THF aqueous solution of 1M HCl. The layers were separated and (40 mL) was then added to the reaction mixture and the the aqueous phase was extracted with Et 2O (twice). The resulting solution was heated at 55 °C for 3 hours. The freshcombined organic fractions were washed with a saturated ly distilled aldehyde (3 mmol), used as first electrophile, was aqueous solution of Na2S2O3, brine, dried over MgSO4, filadded at -50 °C and the mixture was allowed to stir for 2 h. tered and concentrated under reduced pressure. The crude The second electrophile, iodine (1.269 g, 5.0 mmol) in dry was purified by silica-gel chromatography (SiO2, n-hexane / THF (5 mL) was then added at 0 °C and stirred for additionEtOAc, 95:5) to afford 2q as a yellow oil (258 mg, 72%). al 2 hours at that temperature. The reaction mixture was quenched with an aqueous solution of 1M HCl. The layers General procedure for the synthesis of 2u and 2x were separated and the aqueous phase was extracted with A flame-dried 100-mL three-neck flask equipped with a stir Et2O (3 times). The combined organic fractions were washed bar, a low temperature thermometer, a rubber septum and with a saturated aqueous solution of Na2S2O3, brine, dried an inert gas inlet was charged with over MgSO4, filtered and concentrated under reduced pres- bis(cyclopentadienyl)zirconium dichloride (496.5 mg, 1.7 sure. The diastereomeric ratios of 2m and 2n were finally mmol) and dry THF (45 mL) under an inert atmosphere. determined on their respective crude by 13C NMR analyses. After cooling down the stirred reaction suspension to -78 °C, a solution of n-butyllithium (1.4 M in hexanes, 2.4 mL, 3.4 mmol) was added dropwise at that temperature. After stirGeneral procedure for the synthesis of 2 from alkyliring for 1 hour at -78 °C, a 5 mL dry THF solution of the denecyclopropanes 8 substrate 8a (R1 = Et) or 8e (R1 = Pr) (1.0 mmol) was added General procedure for the synthesis of 2o-p from 8a-b dropwise to the solution at -78 °C and the resulting mixture A flame-dried 100-mL three-neck flask equipped with a stir was allowed to slowly warm-up to room temperature overbar, a low temperature thermometer, a rubber septum and night (13 h). The reaction was then heated at 60-65 °C for 5an inert gas inlet was charged with 6 hours. Freshly distilled acetone (367.0 µL, 5.0 mmol), servbis(cyclopentadienyl)zirconium dichloride (496.5 mg, 1.7 ing as first electrophile, was added dropwise to the reaction mmol) and dry Et2O (45 mL) under an inert atmosphere. mixture after cooling down the reaction at 10 °C and the After cooling down the stirred reaction suspension to -78 °C, resulting solution was allowed to stir for 40 min at that a solution of n-butyllithium (1.4 M in hexanes, 2.4 mL, 3.4 temperature. Finally, the reaction mixture was quenched at mmol) was added dropwise at that temperature. After stir- 10 °C with an aqueous solution of 1M HCl and the resulting ring for 1 hour at -78 °C, a 5 mL dry Et2O solution of corre- mixture was stirred for 1 hour. The layers were separated sponding substrate 8a-b (1.0 mmol) was added dropwise to and the aqueous phase was extracted with Et 2O (twice). The the solution at -78 °C and the resulting mixture was allowed combined organic fractions were successively washed with to slowly warm-up to 10 °C overnight (13 h). The reaction water, an aqueous saturated NaHCO3 solution and brine, mixture was thereafter quenched with an aqueous solution dried over MgSO4, filtered and concentrated under reduced of 1M-HCl at rt or DCl (1 M in D2O, 30 mL) at 0 °C. After pressure. The products were isolated by silica-gel chromastirring for 2 hours, the layers were separated and the aque- tography (SiO2, n-hexane / EtOAc, 95:5 – 97:3) as unique ous phase was extracted with Et2O (twice). The combined diastereomers. organic fractions were successively washed with water, an Typical procedure for the synthesis of 2v from 8e aqueous saturated NaHCO3 solution and brine, dried over A flame-dried 100-mL three-neck flask equipped with a stir MgSO4, filtered and concentrated in vacuo. The products bar, a low temperature thermometer, a rubber septum and were isolated by silica-gel chromatography (SiO2, n-hexane, an inert gas inlet was charged with 100%). bis(cyclopentadienyl)zirconium dichloride (496.5 mg, 1.7 Typical procedure for the synthesis of 2q from 8c


Page 17 of 23 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


mmol) and dry THF (45 mL) under an inert atmosphere. After cooling down the stirred reaction suspension to -78 °C, a solution of n-butyllithium (1.4 M in hexanes, 2.4 mL, 3.4 mmol) was added dropwise at that temperature. After stirring for 1 hour at -78 °C, a 5 mL dry THF solution of substrate 8e (R1 = Pr) (186.3 mg, 1.0 mmol) was added dropwise to the solution at -78 °C and the resulting mixture was allowed to slowly warm-up to room temperature overnight (13 h). The reaction was then heated at 60 °C for 6 hours. Paraformaldehyde (124.1 mg, 4.0 mmol) as first electrophile was added to the reaction mixture after cooling down the reaction at 10 °C and the resulting solution was allowed to stir for 2 hours at that temperature. Finally, the reaction mixture was quenched at 10 °C with an aqueous solution of 1M HCl and the resulting mixture was stirred for 1 hour. The layers were separated and the aqueous phase was extracted with Et2O (twice). The combined organic fractions were successively washed with water, an aqueous saturated NaHCO 3 solution and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by silica-gel chromatography (SiO2, n-hexane / EtOAc, 96:4) to afford 2v as a yellow oil (144 mg, 62%). Typical procedure for the synthesis of 2w from 8e A flame-dried 100-mL three-neck flask equipped with a stir bar, a low temperature thermometer, a rubber septum and an inert gas inlet was charged with bis(cyclopentadienyl)zirconium dichloride (496.5 mg, 1.7 mmol) and dry THF (45 mL) under an inert atmosphere. After cooling down the stirred reaction suspension to -78 °C, a solution of n-butyllithium (1.40 M in hexane, 2.4 mL, 3.4 mmol) was added dropwise at that temperature. After stirring for 1 hour at -78 °C, a 5 mL dry THF solution of substrate 8e (R1 = Pr) (186.3 mg, 1.0 mmol) was added dropwise to the solution at -78 °C and the resulting mixture was allowed to slowly warm-up to 10 °C overnight (13 h). Freshly distilled acetone (294 µL, 4.0 mmol), serving as first electrophile was added dropwise at 10 °C and the resulting solution was allowed to stir for 40 min at that temperature. The second electrophile, iodine (1.269 g, 5.0 mmol) in dry THF (5 mL) was then added at 10 °C and stirred for additional 3 hours at that temperature. Finally, the reaction mixture was quenched at 0 °C with an aqueous solution of 1M HCl. The layers were separated and the aqueous phase was extracted with Et2O (twice). The combined organic fractions were washed with a saturated aqueous solution of Na 2S2O3, brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by silica-gel chromatography (SiO2, n-hexane / EtOAc, 97:3) to afford 2w as a yellow oil (239 mg, 62% yield). Determination of the enantiopurity of 2r via an ozonolysis derivatization Substrate 8d was prepared enantioenriched using a previously reported procedure.17g41c-e Enantioenriched compound 2r was synthesized using the same conditions as for 2o. An ozonolysis reaction afforded the corresponding aldehyde whose measured specific rotation was compared to the literature ([α]25D = + 5.00 (c = 10 mg/mL, CDCl3), er evaluated = 98:02).46

Typical procedure for the synthesis of 10 from 2r In an autoclave, 2r (154.3 mg, 1 mmol) was dissolved in 5 mL of Et2O. 1 mol% of Pd/C (10%) was added to the solution and the hydrogenation was performed under 3 atm of H2 overnight. The solution was filtered over celite and the solvent was evaporated. Compound 10 was obtained as colorless oil in 90% yield. All spectroscopic data of 10 was in agreement with those previously reported.47 General procedure for the synthesis of 4 and 5 from ωene-spiropentanes 3 General procedure for the synthesis of 4a, 4ad, 4c, 4cd, 4d, 4f, 4g A flame-dried 50-mL three-neck flask equipped with a stir bar, a low temperature thermometer, a rubber septum and an inert gas inlet was charged with bis(cyclopentadienyl)zirconium dichloride (467.7 mg, 1.6 mmol) and dry Et2O (5 mL) under an inert atmosphere. After cooling down the stirred reaction suspension to -78 °C, a solution of n-butyllithium (1.0 M in hexanes, 3.2 mL, 3.2 mmol) was added dropwise at that temperature. After stirring for 1 hour at -60 °C, a 5 mL dry Et2O solution of substrate 3 (1.0 mmol) was added dropwise to the solution at 78 °C and the resulting mixture was allowed to slowly warmup to room temperature overnight (12 h). The freshly distilled first electrophile (2.5 mmol) was added dropwise after cooling down the reaction mixture to 0 °C and the resulting solution was allowed to stir for 2.5 hour at that temperature. Finally, the reaction mixture was hydrolyzed at 0 °C with an aqueous solution of 1M HCl or DCl. The layers were separated and the aqueous phase was extracted with Et2O (3 times). The combined organic fractions were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The products were isolated by silica-gel chromatography (SiO2, n-hexane / EtOAc, 90:10). General procedure for the synthesis of 4b, 4e and 4h A flame-dried 100-mL three-neck flask equipped with a stir bar, a low temperature thermometer, a rubber septum and an inert gas inlet was charged with bis(cyclopentadienyl)zirconium dichloride (467.7 mg, 1.6 mmol) and dry Et2O (5 mL) under an inert atmosphere. After cooling down the stirred reaction suspension to -78 °C, a solution of n-butyllithium (1.0 M in hexanes, 3.2 ml, 3.2 mmol) was added dropwise at that temperature. After stirring for 1 hour at -60 °C, a 2 mL dry Et2O solution of 3 (1 mmol) was added dropwise to the solution at -78 °C and the resulting mixture was allowed to slowly warm-up to room temperature overnight (13 h). The first electrophile, freshly distilled acetone (184 µL, 2.5 mmol) was added dropwise after cooling the reaction mixture to 0 °C and the resulting solution was allowed to stir for 3 hours at that temperature. The second electrophile, freshly distilled allyl bromide (5.0 mmol, 433 µL), was added to the solution to 0 °C, followed by the addition at that temperature of a dry THF solution (3 mL) of CuI (19.1 mg, 0.1 mmol) and flame-dried LiCl (8.5 mg, 0.2 mmol). The resulting mixture was allowed to stir at 55 °C for 2 hours at which time it was quenched at 0 °C with an aqueous solution of 0.1M HCl. The layers were separated



and the aqueous phase was extracted with Et 2O (3 times). The combined organic fractions were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The products were isolated by silica-gel chromatography (SiO2, n-hexane / EtOAc, 90:10). General procedure for the synthesis of 5a-d A flame-dried 50-mL three-neck flask equipped with a stir bar, a low temperature thermometer, a rubber septum and an inert gas inlet was charged with bis(cyclopentadienyl)zirconium dichloride (356.6 mg, 1.2 mmol) and dry Et2O (5 mL) under an inert atmosphere. After cooling down the stirred reaction suspension to -78 °C, a solution of n-butyllithium (1.0 M in hexanes, 2.4 mL, 2.4 mmol) was added dropwise at that temperature. After stirring for 1 hour at -60 °C, a 5 mL dry Et2O solution of substrate 3 (0.6 mmol) was added dropwise to the solution at 78 °C and the resulting mixture was allowed to slowly warmup to room temperature overnight (12 h). The freshly distilled first electrophile (2.5 mmol) was added dropwise after cooling down the reaction mixture to 0 °C and the resulting solution was allowed to stir for 2.5 hours at that temperature. Anydrous BF3.Et2O (212.9 µL, 1.5 mmol) was then added at 0 °C and the resulting mixture was heated at 40 °C for 5 hours. Finally, the reaction mixture was hydrolyzed at 0 °C with an aqueous solution of 1M HCl or DCl (0.1 M in D2O). The layers were separated and the aqueous phase was extracted with Et2O (3 times). The combined organic fractions were washed with brine, dried over MgSO 4, filtered and concentrated under reduced pressure. The products were isolated by silica-gel chromatography (SiO2, n-hexane / EtOAc, 95:05).

Page 18 of 23

Characterization data of previously unreported compounds (3R*,6R*,E)-6-butyl-2,6-dimethyl-3-propyldeca-4,8,9trien-2-ol (2h). Yellow oil; 126 mg, 53%; E/Z > 98:2; dr = 98:2; Rf = 0.69 (n-pentane / Et2O, 80:20); 1H NMR (300 MHz, CDCl3) δ 0.87 (td, J = 7.2, 2.3 Hz, 6H), 0.97 (s, 3H), 1.11 (s, 3H), 1.13 – 1.16 (m, 2H), 1.17 (s, 3H), 1.19 – 1.37 (m, 8H), 1.68 (s, 1H), 1.89 – 1.96 (m, 1H), 1.99 – 2.06 (m, 2H), 4.60 (dt, J = 6.6, 2.5 Hz, 2H), 4.93 – 5.09 (m, 2H), 5.39 (d, J = 15.7 Hz, 1H). 13 C NMR (75 MHz, CDCl3) δ 13.9, 14.0, 21.1, 23.3, 23.3, 26.4, 26.7, 26.8, 31.6, 39.5, 40.5, 40.6, 54.9, 71.9, 73.4, 86.2, 127.7, 142.9, 209.4. HRMS (ESI-TOF) m/z: calcd for C19H34ONa+ [M + Na]+ 301.2507, found 301.2507. (4R*,7S*,E)-4,7-dimethyl-7-propylundec-5-en-3-ol (2l). Yellow oil; 121 mg, 50%; E/Z > 98:2; dr = 52:48; Rf = 0.33 and 0.44 (n-pentane / Et2O, 90:10).  For Rf = 0.33: 1H NMR (300 MHz, CDCl3) δ 0.83 – 0.88 (m, 6H), 0.91 (s, 3H), 0.93 – 1.00 (m, 6H), 1.09 – 1.28 (m, 10H), 1.31 – 1.43 (m, 1H), 1.58 (dtd, J = 21.3, 7.5, 3.8 Hz, 1H), 1.69 (bs, 1H), 2.07 – 2.19 (m, 1H), 3.23 (ddd, J = 8.0, 6.7, 3.7 Hz, 1H), 5.11 (dd, J = 15.8, 8.7 Hz, 1H), 5.38 (d, J = 15.8 Hz, 1H). 13 C NMR (75 MHz, CDCl3) δ 9.8, 14.0, 14.8, 17.1, 17.2, 23.1, 23.4, 26.3, 26.8, 38.7, 41.0, 43.2, 43.7, 75.9, 128.2, 142.1. HRMS (ESI-TOF) m/z: calcd for C16H33O+ [M + H]+ 241.2531, found 241.2531.

 For Rf = 0.44: 1H NMR (300 MHz, CDCl3) δ 0.83 – 0.89 (m, 6H), 0.90 (s, 3H), 0.92 – 1.00 (m, 1H), 1.11 – 1.42 (m, 1H), 1.48 – 1.61 (m, 2H), 3.34 (ddd, J = 8.9, 5.4, 3.8 Hz, 1H), 5.15 (dd, J = 15.9, 7.7 Hz, 1H), 5.33 (dd, J = 15.9, 0.7 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 10.2, 14.0, 14.8, 15.3, 17.2, 23.1, 23.4, 26.3, 26.7, 38.5, 41.1, 42.4, 43.7, 76.5, 128.7, 140.5. HRMS (ESITOF) m/z calcd for C16H33O+ [M + H]+ 241.2531, found General procedure for the synthesis of 7 from ω-ene- 241.2527. (methoxymethyl) cyclopropane 6 2-((3S*,4R*)-4-isobutyl-4-methylspiro[2.2]pentan-1-

A flame-dried 50-mL three-neck flask equipped with a stir bar, a low temperature thermometer, a rubber septum and an inert gas inlet was charged with bis(cyclopentadienyl)zirconium dichloride (584.6 mg, 2.0 mmol) and dry Et2O (10 mL) under an inert atmosphere. After cooling down the stirred reaction suspension to -78 °C, a solution of n-butyllithium (1.5 M in hexanes, 2.7 mL, 4.0 mmol) was added dropwise at that temperature. After stirring for 1 hour at temperature between -78 °C and -50 °C, a 1 mL dry Et2O solution of substrate 6 (1.0 mmol) was added dropwise to the solution at -50 °C and the resulting mixture was allowed to slowly warm-up to room temperature overnight (5 h). The reaction mixture was then cooled down to 78 °C and acetic acid or AcOD (0.5 mL) was added. After warming up the reaction to room temperature, the reaction was quenched with an aqueous solution of 1M HCl. The layers were separated and the aqueous phase was extracted with Et2O (twice). The combined organic fractions were washed with an aqueous saturated solution Na2CO3, dried over MgSO4, filtered and concentrated in vacuo. The products 7a-d were isolated by silica-gel chromatography (SiO 2, n-hexane or n-hexane, 100%).

yl)ethan-1-ol (IIIa). Pale yellow oil; 1.041 g, 38%; dr = 65:30:5:0; 1H NMR (400 MHz, CDCl3) (mixture of diastereomers) δ 0.28-0.37 (m, 1H), 0.44-0.60 (m, 2H), 0.751.06 (m, 10H), 1.16-1.33 (m, 4H), 1.43-1.51 (m, 1H), 1.57-1.64 (m, 1H), 1.68-1.79 (m, 1H), 3.60-3.73 (m, 2H). 13C NMR (50 MHz, CDCl3) (mixture of diastereomers) δ 10.29, 11.4, 12.3, 13.3, 17.8, 17.9, 18.5, 20.7, 21.0, 22.7, 23.3, 23.5, 26.2, 26.3, 36.1, 46.2, 46.6, 62.8. HRMS (ESI-TOF) m/z: calcd for C12H23O [M + H]+ 183.1749, found 183.1731. 2-((1S*,3R*)-4,4-dimethylspiro[2.2]pentan-1-yl)ethan-1-ol (IIIb). Colorless oil; 1804 mg, 50%; dr = 95:05; 1H NMR (400 MHz, CDCl3) δ 0.34 (t, J = 4.1 Hz, 1H), 0.46 (d, J = 4.5 Hz, 1H), 0.53 (d, J = 3.9 Hz, 1H), 0.78-0.91 (m, 1H), 0.92-1.19 (m, 6H), 1.43-1.57 (m, 2H), 3.60-3.75 (m, 4H). 13C NMR (100 MHz, CDCl3) δ 10.8, 12.9, 16.1, 18.0, 23.4, 23.7, 27.0, 36.3, 63.1. HRMS (ESI-TOF) m/z: calcd for C9H17O+ [M + H]+ 141.1279, found 141.1275. 2-((3S*,4R*)-4-ethyl-4-propylspiro[2.2]pentan-1yl)ethan-1-ol (IIIc). Colorless oil; 437 mg, 48%; dr = 55:45:0:0 (unknown configuration at the quaternary center); both diastereomers are described as a mixture): 1H NMR (400 MHz, CDCl3) δ 0.27-0.36 (m, 1H), 0.38-044 (m, 1H), 0.46-0.53 (m, 1H), 0.76-0.91 (m, 7H), 0.96-1.06 (m, 1H), 1.16-1.37 (m,


Page 19 of 23 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


6H), 1.40-1.51 (m, 1H), 1.53-164 (m, 2H), 3.58-3.73 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 10.4, 10.7, 10.7, 12.4, 12.6, 14.7, 14.8, 16.0, 19.6, 24.4 & 24.4, 26.6, 26.7, 27.3, 27.6, 36.3, 36.4, 36.8, 63.2. HRMS (ESI-TOF) m/z: calcd for C12H23O+ [M + H]+ 183.1749, found 183.1738.

oil; 132 mg, 59%; E/Z > 98:2; dr = 95:05; 1H NMR (400 MHz, CDCl3) δ 0.34 (d, J = 4.4 Hz, 1H), 0.55 (d, J = 4.4 Hz, 1H), 0.85 (t, J = 7.0 Hz, 3H), 1.03 (s, 3H), 1.10 (s, 6H), 1.12-1.23 (m, 7H), 1.28-1.38 (m, 1H), 1.40-1.50 (m, 1H), 1.72 (s, 1H), 1.89 (td, J = 9.6, 2.8 Hz, 1H), 5.09 (dd, J = 15.6, 9.6 Hz, 1H), 5.47 (d, J = 15.6 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 14.3, 19.2 (d, J = (3S*,4R*)-1,1-dimethyl-4-(pent-4-en-1yl)spiro[2.2]pentane (3a). Colorless oil; 660 mg, 62%; dr = 19.1 Hz), 21.6, 22.1, 22.4, 23.3, 26.0, 26.7, 27.9, 28.1, 32.2, 55.2, + 95:5 (relative configuration of the major isomer determined 72.1, 128.4, 140.7. HRMS (ESI-TOF) m/z: calcd for C15H28DO + by NOESY experiments); 1H NMR (400 MHz, CDCl3) δ 0.26 [M + H] 226.2281, found 226.2288. (dd, J = 4.4, 3.9 Hz, 1H), 0.42 (d, J = 4.4 Hz, 1H), 0.53 (d, J = (R*)-3-((E)-2-((S*)-1-(but-3-en-1-yl)-2,24.0 Hz, 1H), 0.78 (dd, J = 8.3, 3.8 Hz, 1H), 0.86-0.96 (m, 1H), dimethylcyclopropyl)vinyl)-2-methylhexan-2-ol (4b). 0.95-1.14 (m, 6H), 1.20-1.34 (m, 2H), 1.36-1.49 (m, 2H), 2.04 Colorless oil; 174 mg, 66%; E/Z > 98:2; dr = 90:10; 1H NMR (m, 2H), 4.82-5.07 (m, 2H), 5.70-5.88 (m, 1H). 13C NMR (100 (400 MHz, CDCl3) δ 0.26 (d, J = 4.5 Hz, 1H), 0.54 (d, J = 4.5 MHz, CDCl3) δ 10.9, 15.7, 15.9, 17.6, 23.3, 23.5, 27.3, 28.8, 32.6, Hz, 1H), 0.85 (t, J = 7.1 Hz, 3H), 0.99 (s, 3H), 1.02-1.53 (m, 33.8, 114.2, 139.2. HRMS (ESI-TOF) m/z: calcd for C12H21+ [M 14H), 1.58-1.70 (m, 2H), 1.95 (ddd, J = 10.6, 9.2, 2.5 Hz, 1H), 2.00-2.16 (m, 2H), 4.83-5.01 (m, 2H), 5.11 (dd, J = 15.4, 9.7 Hz, + H]+ 165.1643, found 165.1663. 1H), 5.51 (d, J = 15.5 Hz, 1H), 5.80 (ddt, J = 17.1, 10.2, 6.8 Hz, (3S*,4R*)-4-(hex-5-en-1-yl)-1,113 dimethylspiro[2.2]pentane (3b). Colorless oil; 252 mg, 1H). C NMR (100 MHz, CDCl3) δ 14.2, 21.5, 21.9, 22.1, 23.5, 78%; dr = 95:5; 1H NMR (400 MHz, CDCl3) δ 0.25 (t, J = 4.1 25.2, 27.2, 31.4, 32.1, 32.3, 33.8, 55.1, 114.2, 131.2, 137.5, 139.4. + + Hz, 1H), 0.42 (d, J = 3.9 Hz, 1H), 0.53 (d, J = 3.9 Hz, 1H), 0.77 HRMS (ESI-TOF) m/z: calcd for C18H33O [M + H] 265.2531, (dd, J = 7.7, 4.3 Hz, 1H), 0.86-0.95 (m, 1H), 0.95-1.15 (m, 6H), found 265.2543. 1.17-1.48 (m, 6H), 1.97-2.09 (m, 2H), 4.86-5.02 (m, 2H), 5.705.89 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 11.06, 15.9, 16.2, 17.8, 23.5, 23.7, 27.5, 29.1, 33.1, 34.0, 114.34, 139.4. HRMS (ESITOF) m/z: calcd for C13H23+ [M + H]+ 179.1800, found: 179.1827.

(R*)-3-ethyl-4-((E)-2-((S*)-1,2,2trimethylcyclopropyl)vinyl)heptan-3-ol (4c). Colorless oil; 191 mg, 76%; E/Z > 98:2; dr = 90:10; (both diastereomers are described as a mixture): 1H NMR (400 MHz, CDCl3) δ 0.33 (t, J = 4.4 Hz, 1H), 0.54 (d, J = 4.4 Hz, 1H), 0.79-0.89 (m, 9H), 0.96-1.69 (m, 18H), 2.06 (ddd, J = 11.8, 9.6, 2.0 Hz, 1H), 5.16 (dd, J = 15.5, 9.7 Hz, 1H), 5.43 (d, J = 15.5 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 7.7, 7.8, 14.3, 19.6, 21.4, 21.5, 22.1, 22.4, 23.3, 26.1, 28.1 & 28.2, 28.5, 28.6, 28.9, 29.1, 31.1 & 31.2, 50.3, 50.4, 75.4, 75.6, 128.4, 139.8. HRMS (ESI-TOF) m/z: calcd for C17H33O+ [M + H]+ 253.2531, found 253.2542.

(3S*,4R*)-4-(hept-6-en-1-yl)-1,1dimethylspiro[2.2]pentane (3c). Colorless oil; 261 mg, 81%; dr =95:5; 1H NMR (400 MHz, CDCl3) δ 0.25 (t, J = 4.1 Hz, 1H), 0.39-0.47 (m, 1H), 0.53 (d, J = 3.9 Hz, 1H), 0.61-0.80 (m, 1H), 0.86-0.95 (m, 1H), 0.95-1.13 (m, 6H), 1.17-1.44 (m, 8H), 1.972.08 (m, 2H), 4.86-5.03 (m, 2H), 5.72-5.86 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 11.0, 15.9, 16.3, 17.8, 23.5, 23.7, 27.5, 29.2, (R*)-4-((E)-2-((S*)-2,2-dimethyl-1-(methyl29.4, 29.5, 33.2, 34.0, 114.3, 139.4. HRMS (ESI-TOF) m/z: d)cyclopropyl)vinyl)-3-ethylheptan-3-ol (4cd). Colorless oil; 200 mg, 79%; E/Z > 98:2; dr = 85:15; (both diastereomers calcd for C14H25+ [M + H]+ 193.1956, found: 193.1973. are described as a mixture): 1H NMR (400 MHz, CDCl3) δ (3S*,4R*)-4-allyl-1-isobutyl-1-methylspiro[2.2]pentane (3d). Colorless oil; 1.309 g, 62%; dr = 65:30:5:0 (relative con- 0.32 (d, J = 4.3 Hz, 1H), 0.54 (d, J = 4.3 Hz, 1H), 0.75-0.93 (m, figuration of the major isomer determined by NOESY experi- 9H), 1.03 (s, 3H), 1.09 (s, 3H), 1.12-1.25 (m, 3H), 1.26-1.65 (s, ments); : 1H NMR (400 MHz, CDCl3) δ 0.32-0.38 (m, 1H), 8H), 2.06 (ddd, J = 11.1, 9.6, 2.4 Hz, 1H), 5.15 (dd, J = 15.5, 9.6 13 0.47-0.51 (m, 1H), 0.60-0.64 (m, 1H), 1.13-1.45 (m, 2H), 1.45- Hz, 1H), 5.41 (minor) & 5.43 (major) (d, J = 15.5 Hz, 1H). C 1.84 (m, 12H), 2.04 (t, J = 6.5 Hz, 2H), 4.95 (d, J = 10.1 Hz, 1H), NMR (100 MHz, CDCl3) δ 7.7, 7.8, 14.3, 14.3, 19.3 (t, J = 19.1 5.06 (d, J = 17.1 Hz, 1H), 5.86 (ddt, J = 16.8, 10.2, 6.5 Hz, 1H). Hz), 21.4, 21.5, 22.0, 22.4, 23.3, 23.4, 26.0, 28.1, 28.2, 28.5, 28.6, 13 C NMR (100 MHz, CDCl3) δ 10.4, 11.5, 15.0, 16.0, 17.8, 17.9, 28.9, 29.1, 31.2, 31.2, 50.3, 50.4, 75.4, 75.6, 128.1, 128.4, 139.9. + 18.6, 18.7, 20.8, 21.0, 22.8, 23.4, 26.4, 26.4, 26.9, 27.0, 37.5, HRMS (ESI-TOF) m/z: calcd for C17H30OD [M – OH] 46.6, 46.8, 114.5, 138.4. HRMS (ESI-TOF) m/z: calcd for 236.2483, found 236.2490. C13H23O [M + H2O]+ 195.1749, found 195.1758. (R*)-2-methyl-3-((E)-2-((S*)-1,2,2trimethylcyclopropyl)vinyl)hexan-2-ol (4a). Colorless oil; 143 mg, 64%; E/Z > 99:1; dr = 95:05; 1H NMR (400 MHz, CDCl3) δ 0.33 (d, J = 4.4 Hz, 1H), 0.55 (d, J = 4.4 Hz, 1H), 0.85 (t, J = 7.2 Hz, 3H), 1.03 (s, 3H), 1.07-1.25 (m, 14H), 1.26-1.51 (m, 2H), 1.73 (s, 1H), 1.92 (ddd, J = 11.1, 9.7, 2.5 Hz, 1H), 5.11 (dd, J = 15.5, 9.7 Hz, 1H), 5.47 (d, J = 15.5 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 14.3, 19.5, 21.6, 22.1, 22.4, 23.3, 26.1, 26.8, 27.3, 28.1, 32.2, 55.2, 72.1, 128.4, 140.7. HRMS (ESI-TOF) m/z: calcd for C15H29O+ [M + H]+ 225.2218, found 225.2225. (R*)-3-((E)-2-((S*)-2,2-dimethyl-1-(methyld)cyclopropyl)vinyl)-2-methylhexan-2-ol (4ad). Colorless

(R*)-2-methyl-3-((E)-2-((S*)-1,2,2trimethylcyclopropyl)vinyl)heptan-2-ol (4d). Colorless oil; 147 mg, 62%; E/Z > 98:2; dr = 80:20; (both diastereomers are described as a mixture): 1H NMR (400 MHz, CDCl3) δ 0.33 (t, J = 4.4 Hz, 1H), 0.54 (d, J = 4.3 Hz, 1H), 0.84 (t, J = 6.8 Hz, 3H), 1.02 (s, 3H), 1.04-1.18 (m, 13H), 1.18-1.36 (m, 4H), 1.45-1.56 (m, 1H), 1.74 (s, 1H), 1.88 (ddd, J = 10.9, 9.6, 2.5 Hz, 1H), 5.10 (dd, J = 15.4, 9.7 Hz, 1H), 5.46 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 14.3, 19.6, 22.1, 22.4, 22.8, 22.8, 23.3, 23.4, 26.0 & 26.1, 26.8 & 26.9, 27.2, 28.1, 28.4, 29.5, 29.6, 30.5, 30.7, 55.4, 72.1, 72.4, 128.2, 128.4, 140.7. HRMS (ESI-TOF) m/z: calcd for C16H31O+ [M + H]+ 239.2375, found: 239.2382.



(R*)-3-((E)-2-((S*)-1-(but-3-en-1-yl)-2,2dimethylcyclopropyl)vinyl)-2-methylheptan-2-ol (4e).

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(E)-3-butyl-2,7,7-trimethyl-6-methyleneoct-4-en-2-ol (5b). Colorless oil; 87 mg, 61%; E/Z > 98:2; 1H NMR (400 MHz, CDCl3) δ 0.85 (t, J = 6.8 Hz, 3H), 1.06 (s, 9H), 1.11-1.38 (m, 11H), 1.51-1.65 (m, 2H), 1.96 (ddd, J = 11.0, 9.9, 2.7 Hz, 1H), 4.73 (s, 1H), 4.95 (s, 1H), 5.56 (dd, J = 15.2, 9.9 Hz, 1H), 6.11 (d, J = 15.3 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 14.3, 22.9, 27.1, 27.5, 29.3, 29.5, 30.6, 35.2, 55.5, 72.6, 107.0, 131.9, 133.8, 156.6. HRMS (ESI-TOF) m/z calcd for C16H31O+ [M + H]+ 239.2375, found: 239.2386.

Colorless oil; 214 mg, 77%; E/Z > 98:2; dr = 95:05; 1H NMR (400 MHz, CDCl3) δ 0.26 (d, J = 4.5 Hz, 1H), 0.55 (d, J = 4.5 Hz, 1H), 0.84 (t, J = 6.9 Hz, 3H), 0.99 (s, 3H), 1.04-1.46 (m, 15H), 1.47-1.57 (m, 1H), 1.59-1.69 (m, 2H), 1.92 (ddd, J = 10.9, 9.7, 2.7 Hz, 1H), 1.99-2.20 (m, 2H), 4.82-5.01 (m, 2H), 5.11 (dd, J = 15.4, 9.7 Hz, 1H), 5.51 (d, J = 15.5 Hz, 1H), 5.80 (ddt, J = 17.2, 10.2, 6.7 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 14.3, 22.0, 22.1, 22.8, 23.5, 25.2, 27.2, 28.5, 30.7, 31.4, 32.4, 33.8, 55.3, 72.3, (E)-2,3,7,7,9-pentamethyl-6-methylenedec-4-en-2-ol 114.2, 131.3, 137.5, 139.4. HRMS (ESI-TOF) m/z: calcd for (5c). Colorless oil; 103 mg, 72%; E/Z > 98:2; 1H NMR (400 C19H35O+ [M + H]+ 279.2688, found 279.2689. MHz, CDCl3) δ 0.74-0.89 (m, 6H), 1.00-1.10 (m, 9H), 1.12-1.23 (m, 6H), 1.27 – 1.32 (m, 2H), 1.54 (m, 2H), 1.70 (bs, 1H), 2.18(R*)-2-methyl-3-((E)-2-((S*)-1,2,2trimethylcyclopropyl)vinyl)octan-2-ol (4f). Colorless oil; 2.25 (m, 1H), 4.71 (d, J = 1.4 Hz, 1H), 5.03 (s, 1H), 5.72-5.80 (m, 13 176 mg, 70%; E/Z > 98:2; dr = 85:15; (both diastereomers are 1H), 6.09 (d, J = 15.3 Hz, 1H). C NMR (100 MHz, CDCl3) δ described as a mixture): 1H NMR (400 MHz, CDCl3) δ 0.33 (t, 15.7, 25.0, 25.1, 27.0, 27.1, 28.4, 28.5, 38.8, 48.8, 50.1, 72.8, J = 4.4 Hz, 1H), 0.56 (d, J = 4.4 Hz, 1H), 0.84 (t, J = 6.8 Hz, 108.4, 131.8, 133.0, 155.1. HRMS (ESI-TOF) m/z: calcd for + 3H), 0.98-1.12 (m, 9H), 1.12-1.35 (m, 13H), 1.43-1.54 (m, 1H), C16H30O [M + H] 238.2296 found 238.2307. (E)-3-ethyl-4,8,8,10-tetramethyl-7-methyleneundec-5en-3-ol (5d). Colorless oil; 108 mg, 68%; E/Z > 98:2; 1H NMR (400 MHz, CDCl3) δ 0.79-0.91 (m, 12H), 0.96-1.09 (m, 9H), 1.12-1.31 (m, 3H), 1.41-1.60 (m, 5H), 2.26-2.40 (m, 1H), 4.71 (d, J = 1.0 Hz, 1H), 5.03 (s, 1H), 5.74-5.88 (m, 1H), 6.05 (d, J = 15.4 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 7.8, 7.9, 14.9, 25.0, (E)-5-((1S*,2R*)-2-isobutyl-1,2-dimethylcyclopropyl)-2,3- 25.0, 25.1, 28.4, 28.4, 28.5, 28.9, 38.9, 44.0, 50.2, 108.2, 131.1, + dimethylpent-4-en-2-ol (4g). Colorless oil; 195 mg, 82%; 133.1, 155.2. HRMS (ESI-TOF) m/z: calcd for C18H34O [M + + E/Z > 98:2; dr = 60:40; (both diastereomers are described as a H] 266.2610, found 266.2613. mixture): 1H NMR (400 MHz, CDCl3) δ, , 0.33 (d, J = 4.5 Hz, 0.4H), 0.35 (d, J = 4.5 Hz, 0.6H), 0.57 (d, J = 4.4 Hz, 0.4H), ASSOCIATED CONTENT 0.61 (d, J = 4.4 Hz, 0.6H), 0.80 – 1.30 (m, 22H), 1.58 – 1.70 (m, Supporting Information 3H), 2.11 – 2.23 (m, 1H), 5.28 (m, 1H), 5.48 (d, J = 6.0 Hz, The Supporting Information is available free of charge on the 0.6H) 5.52 (d, J = 6.0 Hz, 0.4H). 13C NMR (100 MHz, CDCl3) ACS Publications website at DOI: XXXX. δ 15.9, 16.0, 19.3, 19.5, 19.8, 20.1, 22.6, 22.7, 22.7, 22.9, 24.7, Overview of the adopted strategy for the preparation of starting coordinates, 24.8, 25.4, 25.5, 26.0, 26.2, 26.2, 26.3, 26.9, 27.1, 27.2, 27.5, materials, computational details and 1 Cartesian mechanistic experimental details, and H and 13C NMR spectra 43.9, 44.3, 48.6, 48.6, 72.2, 72.3, 129.2, 129.7, 138.5, 138.5. of all new products. HRMS (ESI-TOF) m/z: calcd for C16H30O [M + H]+ 238.2295, found 238.2314. AUTHOR INFORMATION

1.72 (s, 1H), 1.89 (ddd, J = 10.9, 9.7, 2.5 Hz, 1H), 5.10 (dd, J = 15.4, 9.6 Hz, 1H), 5.43 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 14.3, 19.5, 19.6, 22.1, 22.4, 22.5, 22.8, 22.9, 23.3, 23.4, 26.1, 26.8, 26.9, 27.3, 27.9, 28.0, 28.1, 28.4, 29.8, 29.9, 31.9, 32.0, 55.4, 72.1, 72.4, 128.2, 128.5, 140.7. HRMS (ESI-TOF) m/z calcd for C17H33O+ [M + H]+ 253.2531, found 253.2543.

(E)-5-((1S*,2R*)-1-(but-3-en-1-yl)-2-isobutyl-2methylcyclopropyl)-2,3-dimethylpent-4-en-2-ol (4h). Colorless oil; 219 mg, 79%; E/Z > 98:2; dr = 60:40; (both diastereomers are described as a mixture): 1H NMR (400 MHz, CDCl3) δ 0.20-0.32 (m, 1H), 0.53-0.65 (m, 1H), 0.77-1.48 (m, 20H), 1.52-1.84 (m, 3H), 1.94-2.28 (m, 3H), 4.83-5.06 (m, 2H), 5.18-5.35 (m, 1H), 5.45-5.60 (m, 1H), 5.71-5.92 (m, 1H). 13 C NMR (100 MHz, CDCl3) δ 16.1, 16.1, 19.2, 20.3, 22.7, 23.0, 23.0, 23.1, 24.4, 24.4, 24.7, 26.3, 26.9, 26.9, 27.1, 27.1, 31.0, 31.0, 32.3, 32.4, 33.5, 33.8, 43.7, 44.4, 48.7, 48.7, 72.5, 72.6, 114.1, 114.2, 132.1, 132.6, 135.5, 135.5, 139.4, 139.5. HRMS (ESI-TOF) m/z: calcd for C19H34O [M + H]+ 278.2610, found 278.2599.

Corresponding Author * E-mail: [email protected]; Tel: +972-4-8293709. Email: [email protected] Email: [email protected]

Author Contributions ‡ These authors have contributed equally.

ACKNOWLEDGMENT This research is supported by the European Research Council under the European Community’s Seventh Framework Program (ERC agreement no. 338912). S.S. thanks the Planning and Budgeting Committee (PBC) of the Council for Higher Education for providing financial support. LP thanks CCIR of ICBMS and CALMIP for providing computational resources and technical support. I.M. holds the Sir Michael and Lady Sobell Academic Chair.

(E)-2,7,7-trimethyl-6-methylene-3-propyloct-4-en-2-ol (5a). Colorless oil; 79 mg, 59%; E/Z > 98:2; 1H NMR (400 MHz, CDCl3) δ 0.87 (t, J = 7.2 Hz, 3H), 1.06 (s, 9H), 1.11-1.55 (m, 10H), 1.62 (s, 1H), 1.99 (ddd, J = 11.2, 10.1, 2.5 Hz, 1H), 4.73 (s, 1H), 4.95 (s, 1H), 5.57 (dd, J = 15.2, 9.9 Hz, 1H), 6.11 (d, J = 15.3 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 14.3, 21.5, 27.2, 27.5, 29.6, 31.9, 35.2, 55.3, 72.6, 107.0, 131.9, 133.8, 156.6. REFERENCES HRMS (ESI-TOF) m/z: calcd for C15H29O+ [M + H]+ 225.2218, 1 (a) Breslow, R. Acc. Chem. Res. 1980, 13, 170. (b) Breslow, found 225.2215. R. Chem. Soc. Rev. 1972, 1, 553.


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