DOI: 10.1002/chem.201303569

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& Carbometalation

Modulable and Highly Diastereoselective Carbometalations of Cyclopropenes Dorian Didier,[a] Pierre-Olivier Delaye,[a] Marwan Simaan,[a] Biana Island,[a] Guillaume Eppe,[a] Hendrik Eijsberg,[a] Amir Kleiner,[a] Paul Knochel,[b] and Ilan Marek*[a]

Abstract: The copper-catalyzed carbomagnesiation reaction of cyclopropenyl esters 1 leads to various substituted cyclopropanes species 3 in good yields with very high diastereoselectivities. The reaction proceeds through a syn-chelated carbomagnesiation reaction and could be extended to various cyclopropenylmethyl ester derivatives 5. The potential of this approach was illustrated by the preparation of two consecutive all-carbon quaternary stereocenters. However, the carbometalation reaction needs to be performed at temperature ranging from 35 to 20 8C to avoid subsequent fragmentation reaction into stereodefined b,g-nonconjugat-

Introduction Following the pioneering discovery and use of organomagnesium reagents by Grignard in 1900,[1] the formation of carbon– carbon bonds through the use of organometallic species has been widely studied. In the repertoire of C C bond formation with organometallic species, the carbometalation reactions of nonpolarized multiple bonds represent a versatile tool to bifunctionalize unsaturated systems. Indeed, the addition of a carbon–metal bond of an organometallic across a carbon– carbon unsaturated system leading to a new organometallic species that can be further functionalized is called a carbometalation reaction.[2] Among all the possible candidates for carbometalation reactions, organocopper derivatives occupy a significant place due to their high stereo- and chemoselectivity, which enables them to add smoothly to the triple bond of various alkynes even in the presence of other functionalities.[3] Indeed, the carbocupra[a] Dr. D. Didier, Dr. P.-O. Delaye, M. Simaan, B. Island, Dr. G. Eppe, Dr. H. Eijsberg, A. Kleiner, Prof. Dr. I. Marek Schulich Faculty of Chemistry and the Lise Meitner–Minerva Center for Computational Quantum Chemistry Technion–Israel Institute of Technology Technion City, Haifa 32000 (Israel) Fax: (+ 972) 4 829 3709 E-mail: [email protected] [b] Prof. Dr. P. Knochel Department Chemie und Biochemie Ludwig-Maximilians-Universitt, Butenandtstrasse 5–3 81377 Munich (Germany) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201303569. Chem. Eur. J. 2014, 20, 1038 – 1048

ed unsaturated esters 4. Alternatively, the carbocupration reaction with organocopper species could also be performed to leads to configurationally stable cyclopropyl copper species 2[Cu]. Additionally, when the Lewis acid character of the copper center is decreased (i.e., RCuCNLi), the reaction proceed with an anti-selectivity. The diastereodivergent behavior of these organometallic species is of synthetic interest, since both diastereomers syn-3 and anti-3 can be obtained, at will, from the same precursor cyclopropenyl esters 1.

tion of an alkyne usually leads to a single regioisomer, resulting from a syn-addition.[3] Moreover, the regioselectivity of the reaction is typically controlled by the nature of the substituents on the triple bond (Scheme 1). Stereocontrol, regioselectivity, and mechanism have been investigated in detail in the

Scheme 1.

last few decades and summarized in several reviews.[4] Besides forming stereodefined polysubstituted double bonds, the carbometalation reaction of alkynes can also be considered as a starting point for the creation of more complex molecular architectures when subsequent in-situ functionalizations are performed (Scheme 2). In this context, the regio- and diastereoselective carbocupration of a-heterosubstituted alkyne derivatives, such as chiral alkynyl sulfoxides,[5] ynamides,[6] alkynyl ethers[7] and terminal alkynes,[8] led, after addition of Et2Zn, CH2I2, and carbonyl electrophiles, to the formation of acyclic adducts possessing two adjacent sp3 stereocenters, including the challenging all-carbon quaternary stereocenters,[9] in good yields and excellent diastereoselectivities (Scheme 2). Alternatively, the vinyl copper intermediate can also react intramolecularly with oxenoids[10] to give stereodefined b,b-disubstituted

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Scheme 2.

enolates. The addition of aldehydes (or imines) led to the aldol (or Mannich-type) adducts possessing the expected quaternary stereocenter in good yields and high stereoselectivities (Scheme 2).[11] Highly substituted alkyl chains possessing contiguous sp3 stereocenters in acyclic systems could alternatively also be obtained through the carbometalation of appropriate alkenes (Scheme 3). However, such carbometalation reactions are much more challenging than the carbometalation of alkynes, since the carbometalated product is usually of similar reactivity

Scheme 3.

Abstract in Hebrew:

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as that of the starting organometallic species and oligomerization reactions typically occur.[12] Assuming that one can control the addition of an organometallic species across the double bond without further oligomerization, that is, if the reaction is performed on a a,b-disubstituted double bond, the issue of regioselectivity is raised. Furthermore, the addition of an electrophile leads to the creation of two stereogenic centers and issues of diastereoselectivity of the reaction should also be considered.[13] Finally, the asymmetric addition of a carbon nucleophile (enantiofacial differentiation) across an unactivated double bond is still a challenging problem despite the fact that it would acquire a significant utility as a method for the creation of asymmetric vicinal carbon centers in acyclic systems (Scheme 3).[13] As can be deduced from this introductory part, enantioselective carbometalation reactions of unactivated alkenes are scarce and only few and very specific methods were reported in the literature.[14] Alternatively, when strained alkenes, such as cyclopropene (or norbornenes) derivatives are used, the release of strain associated with the carbometalation reaction leads to an easier reaction and the resulting configurationally stable sp3-cyclopropyl organometallic species formed can react diastereoselectively with various electrophiles. For these reasons, carbometalation of cyclopropenes is a field of intense activity and since the pioneering work of Bubnov (carboboration reaction),[15] Lehmkuhl (carbomagnesiation reaction),[16] Eisch (carboalumination reaction),[17] and Negishi (carbocupration and carbozincation reactions),[18] many elegant methods have appeared in the literature.[19] In more recent years, several sophisticated synthesis of diversely substituted cyclopropane derivatives have been reported involving diastereo- and/or enantioselective carbometalation (and hydrometalation) reaction of cyclopropenes.[20] Particularly appealing is the diastereoselective copper-catalyzed syn-carbomagnesiation of 3-hydroxymethylcyclopropenes as an entry to functionalized cyclopropanes with chiral quaternary stereocenters (Scheme 4, Path A).[21] The corresponding cyclopropenyl esters were assumed to be incompatible with Grignard reagents and, therefore, they were subjected to copper-catalyzed carbozincation (Scheme 4, Path B).[22] The results were equivalent, but a large excess of R2Zn is usually necessary to bring the reaction to completion. In this report, we would like to disclose our results in full and demonstrate that despite the presence of the ester, cyclopropenyl derivatives 1 can undergo a copper-catalyzed syn-carbomagnesiation reaction with extremely high diastereoselectivity. Moreover, by changing the nature of the organometallic

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Scheme 4.

species, the opposite anti isomer can also be obtained from the same starting cyclopropenyl esters 1.

Results and Discussion As organomagnesium species can tolerate a broad range of functional groups and in particular esters,[23] we were interested in developing the copper-catalyzed carbomagnesiation of cyclopropyl esters 1. We were pleased to observe that the reaction proceeds very fast under extremely mild conditions (1.3 equiv RMgX, CuI 10 mol %, Et2O, 35 8C, 10 to 30 min) to give the expected cyclopropyl magnesium species 2 that react with various electrophiles to give functionalized cyclopropanes 3 possessing the all-carbon quaternary stereogenic centers as described in Scheme 5. Furthermore, the metal-catalyzed enantioselective cyclopropenation of terminal alkynes with diazoa-

Scheme 5. Chem. Eur. J. 2014, 20, 1038 – 1048

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cetate derivatives and RhII, CoII, or IrII catalysts are well-established methods and as a result, 2-substituted 2-cyclopropenecarboxylic acid esters 1 are easily obtained with excellent enantiomeric ratios and yields.[24] Therefore, from enantiomeric enriched 1, easily prepared from simple terminal alkynes, the formation of substituted cyclopropanes 3, as single diastereoisomers, are easily achieved. It is interesting to note that although phenyl and methyl species are known to react very sluggishly in carbocupration reaction, the strain release generated by the carbocupration of cyclopropenyl ester 1 allows the reaction to proceed quickly and in good yields (Scheme 5, formation of 3 a to 3 e). The formation of the new functionalized cyclopropylmagnesium species was checked by reaction of 2 with various electrophiles such as D3O + (formation of 3 h–3 j, Scheme 5), allylbromide (formation of 3 k–3 r, Scheme 5), propargyl bromide, and acetone (formation of 3 s and 3 t respectively). In all cases, diastereomeric ratios were excellent. The syn-diastereoselectivity of the copper-catalyzed carbomagnesiation was determined by comparison of the formed adducts with authentic samples from literature[21, 22] and can be rationalized by the existence of a chelated transition state between the carbonyl of the ester and the Lewis acid organometallic species (or with its associated salts, Figure 1).[25] Interestingly, even in a more coordinating solvent such as THF, the syn-chelated adducts are formed Figure 1. with the same diastereomeric ratios. The syn-addition of the Grignard species across the double bond could be inferred by the configuration of deuterated species 3 h–3 j (J = 7.9 to 8 Hz). Different copper salts such as CuBr and CuCN could be used with equal efficiency. It is important to note that the copper-catalyzed carbomagnesiation of cyclopropenyl ester 1 has to be carried out at temperature around 35 8C. Indeed, if the reaction is warmed up to 0 8C, a stereospecific fragmentation reaction[26] occurs to give stereodefined b,g-nonconjugated unsaturated esters 4 (Scheme 6). The stereochemistry of the formed alkenes results from a concerted fragmentation mechanism and has been determined by comparison with known similar compounds previously described in the literature.[27] Such a mechanism has been recently invoked in the Fe-catalyzed carboalumination/fragmentation of doubly activated cyclopropenyl carboxylates[27] or in the addition of Grignard reagents to metalated cyclopropenyl diesters.[28] This method offers an easy access to a wide range of stereocontrolled alkenes, simply by permuting the nature of R1 and R2 (on cyclopropene 1 and on the Grignard reagent, respectively) and the E/Z ratio of the double bond is directly related to the diastereoselectivity of the carbometalation reaction.

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Full Paper Table 1. Carbocupration of cyclopropenyl esters 1.

Scheme 6.

Entry

R1

R2[Cu][a]

E X

d.r.[b]

Yield [%][c]

1 2 3 4 5

Hex Hex Hex Pr Hex

MeCu·MgBr2 Me2CuLi BuCu·LiI BuCu·LiI HexCu·LiI

H3O + H3O + H3O + H3O + AllylBr

> 98:2 (3 b) 87:13 (3 b) 97:3 (3 f) 97:3 (3 u) 97:3 (3 v)

72 71 67 70 65

6

Bu

MeCu·MgBr2

97:3:0:0(3 w)

62

7

Bu

MeCu·MgBr2

97:3:0:0(3 w)

52

8

Bu

EtCu·MgBr2

97:3:0:0(3 x)

43

2

[a] R [Cu] reflects the stoichiometry of the reagents rather than the exact structure of the organometallic species. [b] Determined by 1H and 13 C NMR spectroscopy and gas chromatography. [c] Yield of isolated pure products after purification by column chromatography.

Although the copper-catalyzed carbomagnesiation reaction of cyclopropenyl esters 1 proceeds under very mild conditions and with excellent diastereoselectivities, the corresponding cyclopropylmagnesium species 2 has to react with electrophiles the copper-catalyzed carbomagnesiation and organocopper at low temperature ( 35 to 20 8C) to avoid the fragmentaspecies, we then extended our studies to the carbometalation tion into the nonconjugated unsaturated esters 4. Therefore, of cyclopropenylmethyl ester derivatives 5 (Table 2). to expand the potential scope of reactivity of cyclopropylmetal For cyclopropenylmethyl carbamates (R3 = N(iPr)2), organospecies 2 at higher temperature, we hypothesized that the cycopper species generated from alkyllithium with CuBr (Table 2, clopropylcopper species should be more stable towards the entries 1 and 4), with CuI (Table 2, entries 2 and 5) or the fragmentation and we have therefore examined the carbocupcopper-catalyzed carbomagnesiation (Table 2, entries 3 and 6) ration reaction of 1. Various organocopper species were preled to the same syn-directed carbometalation reactions in pared and reacted with 1 as described in Table 1. moderate yields, but in excellent diastereoselectivities. When We were pleased to see that all organocopper species cyclopropenylmethyl esters 5 c,d are used (R2 = Ph, R3 = CH3), added to cyclopropenyl ester 1 to give 3 in good yields and similar diastereomeric ratios than the copper-catalyzed carbothe carbocupration reaction leads to the formation of cyclopromagnesiation reaction (compare Scheme 5 and Table 1) and panes possessing two adjacent all-carbon quaternary stereothat cyclopropyl copper species 2[Cu] is stable even at room centers with an excellent diastereoselectivity (Table 2, entries 7 temperature (no ring fragmentation into b,g-nonconjugated and 8). These last two examples illustrate the potential of the unsaturated esters 4). Various other sources of copper sources carbometalation reaction to generate substrates of higher mosuch as CuI or CuBr·Me2S could be equally used and similar relecular complexity. Indeed, one element of structure that invarsults were obtained. As the consequence of this greater configurational stability, cyclopropylcopTable 2. Carbocupration of cyclopropenylmethyl esters 5. per species 2[Cu] react with electrophiles, such as vinyl sulfone, through a Michael addition/elimination (Table 1, entry 6) and alkynyl sulfone through Entry R1 R2 R3 R4[M][a] d.r.[b] Yield [%][c] a subsequent carbometalation (Table 1, entries 7 and 8) to give 1 Hex (5 a) H N(iPr)2 MeCu·LiBr 97:3 56 (7 a) MeCu·LiI 97:3 60 (7 a) 2 Hex (5 a) H N(iPr)2 the corresponding addition adMeMgBr, CuI (10 mol %) 97:3 63 (7 a) 3 Hex (5 a) H N(iPr) 2 ducts 3 w,x. By decreasing the MeCu·LiBr 97:3 62 (7 b) 4 Pr (5 b) H N(iPr)2 Lewis acid character of the MeCu·LiI 97:3 66 (7 b) 5 Pr (5 b) H N(iPr)2 copper center by using an orgaMeMgBr, CuI (10 mol %) 97:3 65 (7 b) 6 Pr (5 b) H N(iPr)2 MeCu·LiBr 97:3 59 (7 c) 7 Hex (5 c) Ph CH3 nocuprate, the reaction proceeds MeCu·LiBr 97:3 63 (7 d) 8 Pr (5 d) Ph CH 3 with a lower syn-selectivity 4 [a] R [M] reflects the stoichiometry of the reagents rather than the exact structure of the organometallic spe(Table 1, entry 3). cies. [b] Determined by 1H and 13C NMR spectroscopy and gas chromatography. [c] Yield of isolated pure prodEncouraged by the excellent ucts after purification by column chromatography. syn-selectivities obtained with Chem. Eur. J. 2014, 20, 1038 – 1048

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Full Paper iably increases the difficulty of a chemical synthesis is the presence in the target molecule of an all-carbon quaternary stereocenter.[9] The impediment to synthesis presented by such centers arises from the steric congestion imposed by the four attached carbons. This challenge is exacerbated further when more than one stereogenic center is created in the final adducts as in 7 c,d. As described in Table 1, entry 2, when the Lewis acid character of the copper center was decreased by using an organocuprate, the reaction proceeded with a lower syn-selectivity. We were therefore interested in decreasing the electrophilicity of the copper center even further[29] in order to reverse the selectivity of the carbometalation reaction. Indeed, when CuCN was added to MeLi, the lower-order cyanocuprate RCuCNLi is formed,[30] which exhibits a different reactivity towards the cyclopropenyl esters, leading to the opposite diastereoisomer through an anti-directed carbocupration reaction as described in Scheme 7. This ate complex of copper cannot chelate the

Indeed, this slight excess of RLi forms a “higher-order” cyanocuprate (or Lipshutz cuprate) possessing two organic groups bonded to the copper center and the cyanide group bridges two lithium cations (1.4 MeLi for 1 CuCN).[31] These lithium cations serve a chelating unit between the ester and the cuprate species and led to the syn-directed adducts similar to the organocopper and copper-catalyzed carbomagnesiation reaction (Scheme 8).[32]

Scheme 8.

This diastereodivergent carbometalation reaction of cyclopropenyl esters 1 has been used as a new sequence of combined carbometalation/oxidation/selective ring opening of cyclopropanes, allowing for the preparation of aldehydes bearing a-quaternary stereocenters in a one pot-reaction from these readily available starting materials. Both enantiomers of the corresponding aldehydes could be obtained from the same initial cyclopropene ester (Scheme 9).[33]

Scheme 7.

ester moiety and therefore reacts with an anti-selectivity most probably to avoid steric interactions. The diastereodivergent behavior of these organometallic species are of synthetic interest since both diastereomers syn-3 (Scheme 5) and anti-3 (Scheme 7) can be obtained, at will, from the same precursor cyclopropenyl esters 1. This diastereodivergent carbometalation leading to the anti-adducts was extended to various starting cyclopropenyl derivatives with equal efficiency (Scheme 7). Notably, the addition of MeCuCNLi to functionalized cyclopropenyl ester proceeds nicely despite the presence of a ketone in the aliphatic chain (formation of anti-3 z). These carbometalation reactions are not restricted to the introduction of a methyl group. as the addition of BuCuCNLi led to the anti-carbometalated products, in good yields and diastereomeric ratio. The resulting configurationally stable cyclopropyl copper anti-2 could also react with electrophiles as shown by the formation of anti-3 m. However, it is extremely important to have a rigorous stoichiometric ratio between RLi and CuCN to exclusively form RCuCNLi, as a slight excess of RLi (0.4 equiv excess) to the CuCN solution completely changed the stereochemical outcome of the reaction. Chem. Eur. J. 2014, 20, 1038 – 1048

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Scheme 9.

We also investigated whether the carbometalation reaction of strained carbocycles could be extended to cyclobutene ester 8,[34] (Scheme 10). Various organometallic species were tested for the carbometalation, such as copper-catalyzed carbomagnesiation, copper-catalyzed carbozincation, organocopper (in Et2O and in THF) and organocuprate, but none of them gave rise to the desired carbometalated adducts. Clearly, the difference of behavior between cyclopropenes 1 and cyclobutene 8 towards the addition of organometallic species across the cyclic double bond is due to the different strain energy released during the carbometalation reaction (cyclopropene to cyclopropane: 30 kcal mol 1; cyclobutene to cyclobutane: 6 kcal mol 1).[35]

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Full Paper pounds.[24g, 41] Compounds 3 a–3 g, anti-3 b, anti-3 c, anti-3 e, anti-3 y and anti-3 z were previously described.[33]

General procedures Scheme 10.

Conclusion The copper-catalyzed carbomagnesiation reaction of cyclopropenyl esters 1 leads to various substituted cyclopropanes species 3 in good yields with very high diastereoselectivities. The reaction proceeds through a syn-chelated carbomagnesiation reaction and could be extended to various cyclopropenylmethyl ester derivatives 5. The potential of this approach was illustrated by the preparation of two consecutive all-carbon quaternary stereocenters. However, the carbometalation reaction needs to be performed at temperature ranging from 35 to 20 8C to avoid subsequent fragmentation reaction into stereodefined b,g-nonconjugated unsaturated esters 4. Alternatively, the carbocupration reaction with organocopper species could also be performed to leads to configurationally stable cyclopropyl copper species 2[Cu]. Additionally, when the Lewis acid character of the copper center is decreased (i.e., RCuCNLi), the reaction proceed with an anti-selectivity. The diastereodivergent behavior of these organometallic species is of synthetic interest, since both diastereomers syn-3 and anti-3 can be obtained, at will, from the same precursor cyclopropenyl esters 1.

Experimental Section All glassware was flame dried under vacuum, and cooled under argon prior to use. All reactions were carried out under positive pressure of argon. Diethyl ether and THF were dried from PureSolv Purification System (Innovative Technology). Dichloromethane was distilled from CaH2. Copper iodide, copper cyanide, rhodium acetate dimer, methyllithium (1.6 m in diethyl ether), n-butyllithium (1.6 m in hexanes, methylmagnesium bromide (3.0 m in diethyl ether) were commercially available. Phenylmagnesium bromide (1.1 m in diethyl ether), n-butylmagnesium bromide (1.5 m in diethyl ether) and n-hexylmagnesium bromide (1.25 m in diethyl ether) were prepared according to the literature,[37] and freshly titrated before using with menthol/1,10-phenanthroline.[38] Thin-layer chromatography (TLC) was performed using Merck silica gel 60 F254 plates. Column chromatography was performed using Bio-Lab silica gel 60 A (0.040–0.063 mm). 1H and 13C NMR spectra were recorded on Bruker spectrometers DPX200, AV300 , or AVIII400, using CDCl3 (unless otherwise specified) as solvent. For 1H NMR, the abbreviation “app” stands for apparent and “AB” for an AB system. The GC chromatograms were recorded using Varian 3800 apparatus with Varian CP-Sil 8CB column. HPLC chromatograms were recorded using Agilent 1100 Series line with CHIRALPAK AD-H or CHIRALCEL OD. 1,4-dinitrotoluene was used as internal standard for the determination of NMR yields. Cyclopropenes were prepared according to known procedure[39] using alkynes,[40] rhodium acetate dimer and ethyl diazoacetate in CH2Cl2 and are known comChem. Eur. J. 2014, 20, 1038 – 1048

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General procedure A for the copper-catalyzed carbomagnesiation of cyclopropenes: Alkylmagnesium bromide (1.3 equiv) was added dropwise to a suspension of CuI (19 mg, 0.1 mmol) in Et2O (10 mL) and cyclopropene (1.0 mmol) held at 45 8C. The resulting mixture (yellowish) was then stirred at 35 8C (followed by TLC with hexanes/Et2O 19:1 as eluent, ca. 10 min). The electrophile (1.8 equiv, 1.8 mmol) was then added and the reaction was warmed to 20 8C before quenching with aqueous NH4Cl/NH4OH (2:1) solution. The aqueous layer was extracted twice with Et2O. The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. Crude mixtures were then purified by flash chromatography using a hexanes/Et2O mixture. General procedure B for the carbocupration reaction of cyclopropenes with organocopper species (from alkylmagnesium species): Alkylmagnesium bromide (1.3 equiv, 1.3 mmol) was added dropwise to a suspension of CuI (247 mg, 1.3 mmol) in Et2O (8 mL) at 35 8C. The bright yellow solution was stirred at 30 8C for 30 min. Cyclopropene (1.0 equiv, 1.0 mmol in solution in Et2O: 2 mL mmol 1) was then added dropwise at 30 8C. The solution was then stirred at the same temperature until completion (followed by TLC with hexanes/Et2O 19:1 as eluent, ca. 30 min). The reaction was then quenched with aqueous NH4Cl/NH4OH (2:1) solution. The aqueous layer was extracted twice with Et2O. The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. Crude mixtures were then purified by flash chromatography using a hexanes/Et2O mixture. General procedure C for the carbocupration reaction of cyclopropenes with organocopper species (from alkyllithium species): Alkyllithium (1.3 equiv, 1.3 mmol) was added dropwise to a suspension of CuX (X = I, 228 mg, 1.3 mmol or X = Br, 186 mg, 1.3 mmol) in Et2O (8 mL) at 35 8C. The brown solution was stirred at 35 8C for 30 min. Cyclopropene (1.0 equiv, 1.0 mmol in solution in Et2O: 2 mL mmol 1) was then added dropwise at 35 8C. The solution was then stirred at the same temperature until completion (followed by TLC with hexanes/Et2O 19:1 as eluent, ca. 30 min). The reaction was then quenched with aqueous NH4Cl/NH4OH (2:1) solution. The aqueous layer was extracted twice with Et2O. The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. Crude mixtures were then purified by flash chromatography using a hexanes/Et2O mixture. General procedure D for the carbocupration reaction of cyclopropenes with organocuprate (from alkyllithium species): Alkyllithium (1.2 equiv, 1.2 mmol) was added dropwise to a suspension of CuCN (107 mg, 1.2 mmol) in Et2O (10 mL) at 30 8C. The resulting mixture (pale yellow to colorless in the case of MeLi, yellow to brown in the case of nBuLi) was stirred for 30 min at this temperature. Cyclopropene (1 equiv, 1.0 mmol in solution in Et2O: 1 mL mmol 1) was then added dropwise at 30 8C. The solution (yellow in the case of MeLi, orange to brown in the case of nBuLi) was then stirred at the same temperature until completion (followed by TLC with hexanes/AcOEt 9:1 as eluent, ca. 30 min). The reaction was then quenched with aqueous NH4Cl/NH4OH (2:1) solution. The aqueous layer was extracted twice with AcOEt. The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. Crude mixtures

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Full Paper were then purified by flash chromatography using hexanes/AcOEt mixture. General procedure E for the carbocupration reaction of cyclopropenes with 1.4 equivalents RLi and 1 equivalent CuCN: Alkyllithium (1.56 equiv, 1.56 mmol) was added dropwise to a suspension of CuCN (107 mg, 1.2 mmol) in Et2O (10 mL) at 30 8C. The resulting mixture was stirred for 30 min at this temperature. Cyclopropene (1.0 equiv, 1.0 mmol in solution in Et2O: 1 mL mmol 1) was then added dropwise at 30 8C. The solution was then stirred at the same temperature until completion (followed by TLC with hexanes/AcOEt 9:1 as eluent, ca. 30 min). The reaction was then quenched with aqueous NH4Cl/NH4OH (2:1) solution. The aqueous layer was extracted twice with AcOEt. The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. Crude mixtures were then purified by flash chromatography using hexanes/AcOEt mixture.

Compound characterization (1S*,2S*,3R*)-Ethyl 2-ethyl-2-hexyl-(3-2H1) cyclopropane carboxylate (3 h) was prepared according to procedure A: Eluent (hexanes/Et2O 95:5); yield: 65 % (colorless oil); Rf = 0.65 (hexanes/Et2O 95:5); 1H NMR (CDCl3, 300 MHz): d = 0.80 (d, J = 7.9 Hz, 1 H), 0.84 (t, J = 7.4 Hz, 3 H), 0.87 (t, J = 7.1 Hz, 3 H), 1.12–1.38 (m, 12 H), 1.41– 1.45 (m, 2 H), 1.46–1.53 (m, 1 H), 1.55–1.63 (m, 1 H), 4.11 ppm (q, J = 7.1 Hz, 2 H); 13C NMR (CDCl3, 75 MHz): d = 11.0, 14.2, 14.5, 20.6 (t, J = 24.6), 21.7, 22.8, 26.2, 26.3, 29.5, 32.0, 32.3, 36.5, 60.3, 173.0 ppm; HRMS (ESI pos): m/z calcd for C14H26DO2 + [M+H] + : 228.2074; found: 228.2066. (1S*,2R*)-Ethyl 2-butyl-2-ethyl-(3-2H1)cyclopropanecarboxylate (3 i) was prepared according to procedure A: Eluent (hexanes/ Et2O 95:5); yield: 81 % (colorless oil); Rf = 0.46 (hexanes/Et2O 95:5); 1 H NMR (CDCl3, 300 MHz): d = 0.79 (d, J = 7.9 Hz, 1 H), 0.85 (t, J = 7.1 Hz, 3 H), 0.89 (t, J = 7.4 Hz, 3 H), 1.17–1.33 (m, 7 H), 1.35–1.47 (m, 4 H), 1.51–1.56 (m, 1 H), 4.10 ppm (q, J = 7.1 Hz, 2 H); 13C NMR (CDCl3, 75 MHz): d = 10.6, 14.3, 14.5, 20.3 (t, J = 24.5 Hz), 23.0, 26.0, 28.0, 29.0, 29.8, 32.2, 60.3, 173.0 ppm; HRMS (ESI pos): m/z calcd for C12H22DO2 + [M+H] + : 200.1761; found: 200.1758. (1S*,2R*)-Ethyl 2-{2-[(tert-butyldiphenylsilyl)oxy]ethyl}-2-methyl(3-2H1)cyclopropanecarboxylate (3j) was prepared according to procedure A: Eluent (hexanes/Et2O 95:5); yield: 71 % (yellowish oil); Rf = 0.39 (hexanes/Et2O 95:5); 1H NMR (CDCl3, 300 MHz): d = 0.84 (d, J = 8.0 Hz, 1 H), 1.04 (s, 9 H), 1.13 (s, 3 H), 1.22 (t, J = 7.2 Hz, 3 H), 1.52 (d, J = 8.0 Hz, 1 H), 1.56 (t, J = 6.6 Hz, 2 H), 3.72–3.79 (m, 2 H), 4.03–4.16 (m, 2 H), 7.35–7.45 (m, 6 H), 7.65–7.69 (m, 4 H); 13 C NMR (CDCl3, 75 MHz): d = 14.5, 16.4, 19.2, 20.8 (t, J = 24.2 Hz), 21.1, 24.4, 26.0, 26.9, 43.2, 60.3, 61.9, 127.8, 129.7, 133.9, 135.7, 172.9 ppm; HRMS (ESI pos): m/z calcd for C25H33NaDO3 + [M+Na] + : 434.2238; found: 434.2231. (1S*,2S*,3R*)-Ethyl 3-allyl-2-benzyl-2-methylcyclopropanecarboxylate (3 k) was prepared according to procedure A: Eluent (hexanes/Et2O 95:5); yield: 76 % (yellowish oil); Rf = 0.49 (hexanes/Et2O 95:5); 1H NMR (CDCl3, 300 MHz): d = 1.17( s, 3 H), 1.24 (t, J = 7.1 Hz, 3 H), 1.37 (dt, J = 8.8, 7.6 Hz, 1 H), 1.68 (d, J = 8.8 Hz, 1 H), 2.43 (dt, J = 7.6, 1.4 Hz, 1 H), 2.45 (dt, J = 7.6, 1.3 Hz, 1 H), 2.61 (d, J = 13.9 Hz, 1 H), 2.71 (d, J = 13.9 Hz, 1 H), 4.05–4.13 (m, 2 H), 4.96 (dq, J = 10.3, 1.5 Hz, 1 H), 5.05 (dq, J = 17.3, 1.5 Hz, 1 H), 5.81 (ddt, J = 17.3, 10.3, 6.1 Hz, 1 H), 7.17–7.31 ppm (m, 5 H); 13C NMR (CDCl3, 75 MHz): d = 12.1, 14.5, 27.2, 27.5, 29.7, 30.6, 48.0, 59.9, 114.8, 126.5, 128.3, 129.4, 137.7, 139.0, 171.7 ppm; HRMS (ESI pos): m/z calcd for C17H23O2 + [M+H] + : 259.1698; found: 259.1701 (1S*,2R*,3R*)-Ethyl 3-allyl-2-hexyl-2-phenylcyclopropanecarboxylate (3 l) was prepared according to procedure A: Eluent (hexChem. Eur. J. 2014, 20, 1038 – 1048

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anes/Et2O 95:5); yield: 48 % (yellowish oil); Rf = 0.47 (hexanes/Et2O 95:5); 1H NMR (CDCl3, 400 MHz): d = 0.76 (t, J = 6.8 Hz, 3 H), 1.07 (t, J = 7.2 Hz, 3 H), 1.10–1.23 (m, 8 H), 1.34–1.41 (m, 1 H), 1.43–1.56 (m, 2 H), 1.81 (d, J = 8.6 Hz, 1 H), 2.24–2.31 (m, 1 H), 2.35–2.45 (m, 1 H), 3.88–3.99 (m, 2 H), 4.92 (d, J = 10.3 Hz, 1 H), 5.02 (d, J = 17.3 Hz, 1 H), 5.79 (ddt, J = 17.3, 10.3, 6.0 Hz, 1 H), 7.01–7.03 (m, 2 H), 7.12– 7.22 ppm (m, 3 H); 13C NMR (CDCl3, 100 MHz): d = 14.2, 14.4, 22.7, 26.6, 29.3, 29.5, 29.7, 31.9, 32.0, 39.9, 45.1, 60.0, 114.7, 126.6, 127.9, 130.8, 137.7, 138.1, 170.9 ppm; HRMS (ESI pos): m/z calcd for C21H31O2 + [M+H] + : 315.2324; found: 315.2350. (1S*,2S*,3R*)-Ethyl 3-allyl-2-hexyl-2-methylcyclopropanecarboxylate (3 m) was prepared according to procedure A: Eluent (hexanes/Et2O 95:5); yield: 86 % isolated, 93 % without purification, suitable for analysis (yellowish oil); Rf = 0.56 (hexanes/Et2O 95:5); 1 H NMR (CDCl3, 400 MHz): d = 0.86 (t, J = 6.8 Hz, 3 H), 1.13 (q, J = 8.0 Hz, 1 H), 1.17 (s, 3 H), 1.20–1.37 (m, 13 H), 1.42 (d, J = 8.8 Hz, 1 H), 2.37–2.41 (m, 2 H), 4.04–4.10 (m, 2 H), 4.94 (dd, J = 10.2, 1.3 Hz, 1 H), 5.03 (dd, J = 17.2, 1.3 Hz, 1 H), 5.80 ppm (ddt, 17.2, 10.2, 6.2 Hz, 1 H); 13C NMR (CDCl3, 100 MHz): d = 11.6, 14.2, 14.5, 22.7, 26.5, 27.5, 28.0, 28.0, 29.4, 31.8, 32.0, 43.1, 59.7, 114.5, 138.0, 171.9 ppm; HRMS (ESI pos): m/z calcd for C16H29O2 + [M+H] + : 253.2168; found: 253.2150. (1S*,2S*,3R*)-Ethyl 3-allyl-2-butyl-2-methylcyclopropanecarboxylate (3 n) was prepared according to procedure A: Eluent (hexanes/Et2O 95:5); yield: 80 % isolated, 93 % without purification, suitable for analysis (yellowish oil); Rf = 0.55 (hexanes/Et2O 95:5); 1 H NMR (CDCl3, 300 MHz): d = 0.88 (t, J = 7.1 Hz, 3 H), 1.14 (dt, J = 8.5, 7.4 Hz, 1 H), 1.19 (s, 3 H), 1.23 (t, J = 7.1 Hz, 3 H), 1.25–1.39 (m, 6 H), 1.43 (d, J = 8.8 Hz, 1 H), 2.37–2.45 (m, 2 H), 3.99–4.15 (m, 2 H), 4.95 (dq, J = 10.3, 1.7 Hz, 1 H), 5.04 (dq, J = 17.1, 1.7 Hz, 1 H), 5.82 ppm (ddt, J = 17.1, 10.3, 6.2 Hz, 1 H); 13C NMR (CDCl3, 75 MHz): d = 11.6, 14.3, 14.5, 22.9, 27.5, 28.0, 28.7, 29.5, 31.9, 42.9, 59.8, 114.6, 138.0, 172.0 ppm; HRMS (ESI pos): m/z calcd for C14H25O2 + [M+H] + 225.1855; found: 225.1837. (1S*,2S*,3R*)-Ethyl 3-allyl-2-ethyl-2-methylcyclopropanecarboxylate (3 o) was prepared according to procedure A: Eluent (hexanes/Et2O 95:5); yield: 89 % (yellowish oil); Rf = 0.54 (hexanes/Et2O 95:5); 1H NMR (CDCl3, 300 MHz): d = 0.88 (t, J = 7.4 Hz, 3 H), 1.09 (dt, J = 8.9, 7.4 Hz, 1 H), 1.14 (s, 3 H), 1.18 (t, J = 7.1 Hz, 3 H), 1.26 (q, J = 7.4 Hz, 2 H), 1.38 (d, J = 8.9 Hz, 1 H), 2.31–2.40 (m, 2 H), 3.97–4.06 (m, 2 H), 4.89 (d, J = 10.9 Hz, 1 H), 4.99 (d, J = 16.8 Hz, 1 H), 5.76 ppm (ddt, J = 16.8, 10.4, 6.3 Hz, 1 H); 13C NMR (CDCl3, 75 MHz): d = 10.5, 11.0, 14.4, 27.4, 27.7, 30.3, 31.6, 35.6, 59.6, 114.4, 137.8, 171.7 ppm; HRMS (ESI pos): m/z calcd for C12H21O2 + [M+H] + : 197.1542; found: 197.1522. (1S*,2R*,3R*)-Ethyl 3-allyl-2-butyl-2-ethylcyclopropanecarboxylate (3p) was prepared according to procedure A: Eluent (hexanes/Et2O 95:5); yield: 77 % as a 95:5 mixture of diastereoisomers syn-2 s and anti-2 s (yellowish oil); Rf = 0.47 (hexanes/Et2O 95:5); 1 H NMR (CDCl3, 400 MHz): d = 0.86–0.91 (m, 6 H), 1.10–1.19 (m, 3 H), 1.23 (t, J = 7.1 Hz, 3 H), 1.26–1.33 (m, 3 H), 1.41 (d, J = 8.6 Hz, 1 H), 1.44–1.51 (m, 1 H), 1.63–1.68 (m, 2 H), 2.43–2.46 (m, 2 H), 4.06 (q, J = 7.1 Hz, 2 H), 4.94 (d, J = 10.3 Hz, 1 H), 5.04 (d, J = 17.2 Hz, 1 H), 5.80 ppm (ddt, J = 17.2, 10.3, 6.2 Hz, 1 H); 13C NMR (CDCl3, 100 MHz): d = 10.3, 14.2, 14.5, 23.1, 23.2, 27.5, 28.0, 29.0, 32.2, 32.4, 34.6, 59.8, 114.6, 138.2, 171.9 ppm; HRMS (ESI pos): m/z calcd for C12H21O2 + [M+H] + : 239.2011; found: 239.2032. (1S*,2S*,3R*)-Ethyl 3-allyl-2-{2-[(tert-butyldiphenylsilyl)oxy]ethyl}-2-methylcyclopropanecarboxylate (3q) was prepared according to procedure A: Eluent (hexanes/Et2O 95:5); yield: 72 % (yellowish oil); Rf = 0.32 (hexanes/Et2O 95:5); 1H NMR (CDCl3, 300 MHz): d = 1.06 (s, 9 H), 1.14–1.20 (m, 1 H), 1.19 (s, 3 H), 1.23 (t, J = 7.1 Hz, 3 H), 1.52–1.60 (m, 3 H), 2.38–2.42 (m, 2 H), 3.73–3.80 (m, 2 H), 3.98–

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Full Paper 4.16 (m, 2 H), 4.95 (dq, J = 10.3, 1.5 Hz, 1 H), 5.03 (dq, J = 17.3, 1.5 Hz, 1 H), 5.80 (ddt, J = 17.3, 10.3, 6.1 Hz, 1 H), 7.36–7.44 (m, 6 H), 7.66–7.69 ppm (m, 4 H); 13C NMR (CDCl3, 75 MHz): d = 11.8, 14.4, 19.2, 26.9, 27.3, 27.5, 27.6, 31.3, 45.3, 59.9, 61.8, 114.7, 127.8, 129.8, 133.8, 135.7, 137.8, 171.9 ppm; HRMS (ESI pos): m/z calcd for C28H38O3NaSi + [M+Na] + : 473.2488; found: 473.2480. (1S*,2S*,3R*)-Ethyl 3-allyl-2-[2-(benzyloxy)ethyl]-2-methylcyclopropanecarboxylate (3 r) was prepared according to procedure A: Eluent (hexanes/Et2O 95:5); yield: 68 % (yellowish oil); Rf = 0.42 (hexanes/Et2O 95:5); 1H NMR (CDCl3, 300 MHz): d = 1.12–1.20 (m, 7 H), 1.48 (d, J = 8.9 Hz, 1 H), 1.58 (td, J = 6.8, 2.1 Hz, 2 H), 2.31–2.37 (m, 2 H), 3.51 (t, J = 6.8 Hz, 2 H), 3.95–4.07 (m, 2 H), 4.42 (s, 2 H), 4.88 (dq, J = 10.2, 1.7 Hz, 1 H), 4.97 (dq, J = 17.2, 1.7 Hz, 1 H), 5.74 (ddt, J = 17.2, 10.2, 6.3 Hz, 1 H), 7.17–7.30 ppm (m, 5 H); 13C NMR (CDCl3, 75 MHz): d = 11.9, 14.5, 27.1, 27.3, 27.6, 31.4, 42.5, 59.9, 68.3, 73.2, 114.7, 127.6, 127.7, 128.4, 137.8, 138.5, 171.7 ppm; HRMS (ESI pos): m/z calcd for C19H27O3 + [M+H] + : 303.1960; found: 303.1971. (1S*,2S*,3R*)-Ethyl 2-hexyl-2-methyl-3-(propa-1,2-dien-1-yl)cyclopropanecarboxylate (3 s) was prepared according to procedure A: Eluent (hexanes/Et2O 95:5); yield: 63 % (yellowish oil); Rf = 0.63 (hexanes/Et2O 95:5); 1H NMR (CDCl3, 300 MHz): d = 0.87 (t, J = 6.6 Hz, 3 H), 1.15–1.18 (m, 1 H), 1.22 (s, 3 H), 1.24–1.38 (m, 12 H), 1.65 (d, J = 8.5 Hz, 1 H), 1.73–1.79 (m, 1 H), 4.06–4.14 (m, 2 H), 4.74 (d, J = 6.7 Hz, 2 H), 5.52 ppm (dt, J = 9.6, 6.7 Hz, 1 H); 13C NMR (CDCl3, 75 MHz): d = 12.0, 14.2, 14.5, 22.8, 26.3, 29.4, 30.2, 30.3, 31.7, 32.0, 42.6, 60.1, 75.3, 85.9, 171.2, 210.4 ppm; HRMS (ESI pos): m/z calcd for C16H27O2 + [M+H] + : 251.2011; found: 251.2009. (1S*,5R*,6S*)-6-Hexyl-4,4,6-trimethyl-3-oxabicyclo[3.1.0]hexan-2one (3 t) was prepared according to procedure A: Eluent (hexanes/Et2O 95:5); yield: 79 % (yellowish oil); Rf = 0.17 (hexanes/Et2O 95:5); 1H NMR (CDCl3, 300 MHz): d = 0.86 (t, J = 6.8 Hz, 3 H), 1.00– 1.12 (m, 1 H), 1.21–1.27 (m, 7 H), 1.28 (s, 3 H), 1.34–1.39 (m, 2 H), 1.42 (s, 6 H), 1.72 (d, J = 6.0 Hz, 1 H), 1.97 ppm (d, J = 6.0 Hz, 1 H); 13 C NMR (CDCl3, 75 MHz): d = 14.2, 14.7, 22.7, 22.7, 26.4, 29.3, 29.5, 31.0, 31.8, 31.8, 38.5, 40.3, 83.0, 174.4 ppm; HRMS (ESI pos): m/z calcd for C14H25O2 + [M+H] + : 225.1855; found: 225.1825. (1S*,2R*)-Ethyl 2-butyl-2-propylcyclopropanecarboxylate (3 u) was prepared according to procedure C: Eluent (hexanes/Et2O 95:5); yield: 70 % (colorless oil); Rf = 0.63 (hexanes/Et2O 95:5); 1 H NMR (CDCl3, 300 MHz): d = 0.80 (dd, J = 7.9, 4.3 Hz, 1 H), 0.86 (t, J = 7.2 Hz, 3 H), 0.88 (t, J = 6.9 Hz, 3 H), 1.03 (dd, J = 5.6, 4.3 Hz, 1 H), 1.10–1.20 (m, 2 H), 1.22–1.30 (m, 6 H), 1.31–1.39 (m, 4 H), 1.43 (dd, J = 7.9, 5.6 Hz, 1 H), 1.47–1.54 (m, 1 H), 4.10 ppm (q, J = 7.2 Hz, 2 H); 13 C NMR (CDCl3, 75 MHz): d = 14.3, 14.3, 14.5, 19.6, 20.9, 23.0, 26.2, 28.5, 29.1, 31.1, 39.3, 60.3, 173.0 ppm; HRMS (ESI pos): m/z calcd for C13H25O2 [M+H] + : 213.1855; found: 213.1845. (1S*,3R*)-Ethyl 3-allyl-2,2-dihexylcyclopropanecarboxylate (3 v) was prepared according to procedure C: Eluent (hexanes/Et2O 95:5); yield: 65 % (colorless oil); Rf = 0.52 (hexanes/Et2O 95:5); 1 H NMR (CDCl3, 300 MHz): d = 0.84–0.90 (m, 6 H), 1.17–1.19 (m, 1 H), 1.21–1.39 (m, 22 H), 1.40–1.50 (m, 3 H), 2.04–2.23 (m, 2 H), 4.10 (q, J = 7.1 Hz, 2 H), 4.98 (dq, J = 10.2, 1.6 Hz, 1 H), 5.04 (dq, J = 17.1, 1.6 Hz, 1 H), 5.83 ppm (ddt, J = 17.1, 10.2, 6.4 Hz, 1 H); 13C NMR (CDCl3, 75 MHz): d = 14.2, 14.2, 14.5, 22.8, 22.8, 26.6, 26.6, 29.6, 29.7, 30.1, 31.6, 32.0, 32.0, 32.1, 32.3, 32.5, 36.0, 60.3, 115.1, 137.4, 172.9 ppm; HRMS (ESI pos): m/z calcd for C12H39O2 + [M+H] + : 323.2950; found: 323.2910. (1S*,2S*,3R*)-Ethyl 2-butyl-2-methyl-3-[(E)-1-tosylhex-1-en-2-yl]cyclopropanecarboxylate (3w) was prepared according to procedure B: Eluent (hexanes/Et2O 95:5); yield: 52 % isolated (colorless oil); Rf = 0.15 (hexanes/Et2O 95:5); 1H NMR (CDCl3, 400 MHz): d = 0.85 (t, J = 7.1 Hz, 3 H), 0.90 (t, J = 6.7 Hz, 3 H), 0.94(s, 3 H), 1.14–1.43 Chem. Eur. J. 2014, 20, 1038 – 1048

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(m, 11 H), 1.49–1.65 (m, 3 H), 1.69 (d, J = 6.1 Hz, 1 H), 2.14 (d, J = 6.1 Hz, 1 H), 2.43 (s, 3 H), 2.73–2.79 (m, 1 H), 4.11 (q, J = 7.1 Hz, 2 H), 6.00 (s, 1 H), 7.31 (d, J = 8.0 Hz, 2 H), 7.77 ppm (d, J = 8.0 Hz, 2 H);13C NMR (CDCl3, 100 MHz): d = 13.9, 14.2, 14.4, 18.2, 21.7, 22.9, 23.1, 29.2, 30.0, 31.2, 32.7, 33.8, 35.2, 39.1, 60.9, 127.1, 127.3, 130.0, 139.7, 144.2, 156.9, 171.1 ppm; HRMS (ESI pos): m/z calcd for C24H36O4SNa + [M+Na] + 443.2232; found: 443.2274. (1S*,2S*,3R*)-Ethyl 2-butyl-2-ethyl-3-[(E)-1-tosylhex-1-en-2-yl]cyclopropanecarboxylate (3x) was prepared according to procedure C: Eluent (hexanes/Et2O 95:5); yield: 43 % isolated (colorless oil); Rf = 0.15 (hexanes/Et2O 95:5); 1H NMR (CDCl3, 300 MHz): d = 0.79–0.90 (m, 9 H), 1.01 (q, J = 7.2 Hz, 2 H), 1.21–1.44 (m, 12 H), 1.49–1.54 (m, 2 H), 1.66 (d, J = 6.3 Hz, 1 H), 2.17 (d, J = 6.3 Hz, 1 H), 2.41 (s, 3 H), 2.87–2.97 (m, 1 H), 4.09 (q, J = 7.2 Hz, 2 H), 6.00 (s, 1 H), 7.31 (d, J = 8.2 Hz, 2 H), 7.75 ppm (d, J = 8.2 Hz, 2 H); 13C NMR (CDCl3, 100 MHz): d = 11.0, 14.0, 14.3, 14.5, 21.8, 23.1, 23.2, 23.7, 29.1, 29.3, 30.6, 31.2, 33.0, 39.4, 40.3, 61.0, 127.2, 127.4, 130.0, 139.8, 144.3, 157.0, 171.1; HRMS (ESI pos): m/z calcd for C25H38O4SNa + [M+Na] + 457.2389; found: 457.2364. (1S*,2R*,3S*)-Ethyl 3-allyl-2-hexyl-2-methylcyclopropanecarboxylate (3 manti) was prepared according to procedure D: Eluent (hexanes/Et2O 95:5); yield: 63 % (yellowish oil); Rf = 0.55 (hexanes/Et2O 95:5); 1H NMR (CDCl3, 400 MHz): d = 0.84 (t, J = 6.8 Hz, 3 H), 1.10 (s, 3 H), 1.18–1.25 (m, 11 H), 1.29–1.54 (m, 4 H), 2.02–2.09 (m, 1 H), 2.13–2.20 (m, 1 H), 4.08 (q, J = 7.2 Hz, 2 H), 4.96 (d, J = 10.1 Hz, 1 H), 5.02 (d, J = 17.2 Hz, 1 H), 5.81 ppm (ddt, J = 17.2, 10.1, 6.2 Hz, 1 H); 13 C NMR (CDCl3, 100 MHz): d = 14.1, 14.4, 18.4, 22.7, 26.9, 29.5, 29.5, 31.9, 32.0, 32.4, 32.7, 34.3, 60.2, 115.0, 137.2, 172.8 ppm; HRMS (ESI pos): m/z calcd for C16H29O2 + [M+H] + : 253.2168; found: 253.2156. (1 R*,2S*)-Ethyl 2-benzyl-2-butylcyclopropanecarboxylate (3 y) was prepared according to procedure E: Eluent (hexanes/Et2O 95:5); yield: 65 % (colorless oil); Rf = 0.39 (hexanes/Et2O = 98:2); d.r.: 93:7, determined by GC analysis using Varian CP-Sil 8CB column (injector 280 8C, column oven: 70 8C hold for 1 min, then 5 8C min 1 until 250 8C, flow: 1 mL min 1) tR (major) = 19.8 min, tR (minor) = 19.9 min; 1H NMR (300 MHz, CDCl3, major diastereoisomer): d = 0.82 (t, J = 7.1 Hz, 3 H), 0.96 (dd, J = 8.0, 4.5 Hz, 1 H), 1.10 (dd, J = 5.6, 4.5 Hz, 1 H), 1.15–1.27 (m, 6 H), 1.36–1.53 (m, 3 H), 1.60 (dd, J = 8.0, 5.6 Hz, 1 H), 2.54 (dAB, J = 14.3 Hz, 1 H), 2.79 (dAB, J = 14.3 Hz, 1 H), 4.10 (q, J = 7.1 Hz, 2 H), 7.14–7.29 ppm (m, 5 H); 13C NMR (75 MHz, CDCl3): d = 14.2, 14.5, 19.7, 22.8, 25.4, 29.1, 29.1, 31.5, 42.3, 60.4, 126.4, 128.3, 129.4, 138.9, 172.7 ppm; HRMS (ESI pos): m/z calcd for C17H25O2 [M+H] + : 261.1855; found: 261.1832. (1S*,2S*)-Ethyl 2-methyl-2-(4-oxooctyl)cyclopropanecarboxylate (3 z) was prepared according to procedure E: Eluent (hexanes/ AcOEt 95:5); yield: 76 % (colorless oil); Rf = 0.26 (hexanes/Et2O = 90:10); d.r.: 97:3, determined by GC analysis using Varian CP-Sil 8CB column (injector 280 8C, column oven: 70 8C hold for 1 min, then 5 8C min 1 until 250 8C, flow: 1 mL min 1) tR (major) = 19.1 min, tR (minor) = 19.6 min; 1H NMR (300 MHz, CDCl3, major diastereoisomer): d = 079 (dd, J = 8.1, 4.4 Hz, 1 H), 0.87 (t, J = 7.3 Hz, 3 H), 1.02 (dd, J = 5.5, 4.4 Hz, 1 H), 1.14 (s, 3 H), 1.18–1.33 (m, 7 H), 1.43 (dd, J = 8.0, 5.5 Hz, 1 H), 1.48–1.54 (m, 2 H), 1.60–1.70 (m, 2 H), 2.36 (t, J = 7.4 Hz, 2 H), 2.37 (t, J = 7.3 Hz, 2 H), 4.03–4.14 ppm (m, 2 H); 13 C NMR (100 MHz, CDCl3): d = 13.9, 14.5, 16.0, 20.8, 21.1, 22.5, 26.1, 26.4, 26.4, 40.2, 42.3, 42.7, 60.3, 172.6, 211.1 ppm; HRMS (ESI pos): m/z calcd for C15H27O3 [M+H] + : 255.1960; found: 255.1944. (E)-Ethyl 4-methyldec-3-enoate (4 a) was prepared according to procedure A and then warmed to room temperature before hydrolysis: Eluent (hexanes/Et2O 95:5); yield: 82 % isolated, 91 % without purification, suitable for analysis (colorless oil); Rf = 0.48 (hexanes/Et2O 95:5); 1H NMR (CDCl3, 300 MHz): d = 0.87 (t, J = 6.8 Hz, 3 H), 1.22–1.32 (m, 9 H), 1.34–1.44 (m, 2 H), 1.61 (s, 3 H),

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Full Paper 1.98–2.03 (m, 2 H), 3.02 (d, J = 7.0 Hz, 2 H), 4.12 (q, J = 7.2 Hz, 2 H), 5.30 ppm (t sext, J = 7.1, 1.3 Hz, 1 H); 13C NMR (CDCl3, 75 MHz): d = 14.2, 14.3, 16.4, 22.8, 27.8, 29.0, 31.9, 33.9, 39.7, 60.6, 115.6, 139.5, 172.7 ppm; HRMS (ESI pos): m/z calcd for C13H25O2 + [M+H] + : 213.1855; found: 213.1845. (E)-Ethyl 4-methyloct-3-enoate (4 b) was prepared according to procedure A and then warmed to room temperature before hydrolysis: Eluent (hexanes/Et2O 95:5); yield: 78 % (colorless oil). Rf = 0.48 (hexanes/Et2O 95:5); 1H NMR (CDCl3, 300 MHz): d = 0.87 (t, J = 7.2 Hz, 3 H), 1.21–1.29 (m, 5 H), 1.32–1.41 (m, 2 H), 1.59 (s, 3 H), 1.97–2.02 (m, 2 H), 3.00 (d, J = 7.1 Hz, 2 H), 4.11 (q, J = 7.2 Hz, 2 H), 5.29 (t sext, J = 7.1, 1.3 Hz, 1 H); 13C NMR (CDCl3, 75 MHz): d = 14.1, 14.3, 16.3, 22.4, 33.9, 39.3, 60.5, 115.6, 139.4, 172.6 ppm; HRMS (ESI pos): m/z calcd for C11H21O2 + [M+H] + : 185.1542; found: 185.1533. (E)-Ethyl 4-methylhept-3-enoate (4 c) was prepared according to procedure A and then warmed to room temperature before hydrolysis: Eluent (hexanes/Et2O 95:5); yield: 75 % (colorless oil); Rf = 0.49 (hexanes/Et2O 95:5); 1H NMR (CDCl3, 300 MHz): d = 0.86 (t, J = 7.3 Hz, 3 H), 1.25 (t, J = 7.2 Hz, 3 H), 1.36–1.49 (m, 2 H), 1.61 (s, 3 H), 2.00 (t, J = 7.5 Hz, 2 H), 3.03 (d, J = 7.0 Hz, 2 H), 4.13 (q, J = 7.2 Hz, 2 H), 5.31 ppm (t sext, 7.1, 1.3 Hz, 1 H); 13C NMR (CDCl3, 75 MHz): d = 13.8, 14.4, 16.3, 21.0, 340, 41.8, 60.6, 115.9, 139.2, 172.7 ppm; HRMS (ESI pos): m/z calcd for C10H19O2 + [M+H] + : 171.1385; found: 171.1375. (E)-Ethyl 4-methyl-5-phenylpent-3-enoate (4 d) was prepared according to procedure A and then warmed to room temperature before hydrolysis: Eluent (hexanes/Et2O 95:5); yield: 65 % (colorless oil); Rf = 0.43 (hexanes/Et2O 95:5); 1H NMR (CDCl3, 300 MHz): d = 1.26 (t, J = 7.1 Hz, 3 H), 1.55 (s, 3 H), 3.07 (d, J = 7.2 Hz, 2 H), 3.33 (s, 2 H), 4.14 (q, J = 7.1 Hz, 2 H), 5.47 (t sext, J = 7.1, 1.2 Hz, 1 H), 7.16–7.30 ppm (m, 5 H); 13C NMR (CDCl3, 75 MHz): d = 14.3, 16.2, 34.0, 46.1, 60.7, 118.0, 126.2, 128.4, 129.0, 138.3, 139.8, 172.4 ppm; HRMS (ESI pos): m/z calcd for C14H19O2 + [M+H] + : 219.1385; found: 219.1379. (Z)-Ethyl 4-methyloct-3-enoate (4 e) was prepared according to procedure A and then warmed to room temperature before hydrolysis: Eluent (hexanes/Et2O 95:5); yield: 76 % (colorless oil); Rf = 0.51 (hexanes/Et2O 95:5); 1H NMR (CDCl3, 300 MHz): d = 0.87–0.92 (m, 3 H), 1.23–1.38 (m, 7 H), 1.72 (s, 3 H), 1.98–2.03 (m, 2 H), 3.02 (d, J = 7.1 Hz, 2 H), 4.12 (q, J = 7.1 Hz, 2 H), 5.28–5.33 ppm (m, 1 H); 13 C NMR (CDCl3, 75 MHz): d = 14.2, 14.3, 22.8, 23.6, 30.1, 31.9, 33.7, 60.6, 116.2, 139.7, 172.7 ppm; HRMS (ESI pos): m/z calcd for C11H21O2 + [M+H] + : 185.1542; found: 185.1530. (Z)-Ethyl 4-propyloct-3-enoate (4 f) was prepared according to procedure A and then warmed to room temperature before hydrolysis: Eluent (hexanes/Et2O 95:5); yield: 81 % (colorless oil); Rf = 0.46 (hexanes/Et2O 95:5); 1H NMR (CDCl3, 300 MHz): d = 0.87 (t, J = 7.3 Hz, 3 H), 0.89 (t, J = 7.0 Hz, 3 H), 1.25 (t, J = 7.1 Hz, 3 H), 1.29–1.36 (m, 4 H), 1.38–1.45 (m, 2 H), 1.97–2.02 (m, 4 H), 3.04 (d, J = 7.2 Hz, 2 H), 4.13 (q, J = 7.1 Hz, 2 H), 5.30 ppm (t, J = 7.1 Hz, 1 H); 13C NMR (CDCl3, 75 MHz): d = 14.0, 14.2, 14.4, 21.2, 23.0, 30.2, 30.6, 33.7, 39.1, 60.6, 115.8, 143.5, 172.8 ppm; HRMS (ESI pos): m/z calcd for C13H25O2 + [M+H] + : 213.1855; found: 213.1864. (E)-Ethyl 4-ethyloct-3-enoate (4 g) was prepared according to procedure A and then warmed to room temperature before hydrolysis: Eluent (hexanes/Et2O 95:5); yield: 73 % (colorless oil); Rf = 0.49 (hexanes/Et2O 95:5); 1H NMR (CDCl3, 400 MHz): d = 0.88 (t, J = 7.1 Hz, 3 H), 0.95 (t, J = 7.6 Hz, 3 H), 1.24 (t, J = 7.1 Hz, 3 H), 1.27–1.31 (m, 2 H), 1.34–1.41 (m, 2 H), 2.00–2.05 (m, 4 H), 3.03 (d, J = 7.2 Hz, 2 H), 4.12 (q, J = 7.1 Hz, 2 H), 5.26 ppm (t, J = 7.2 Hz, 1 H); 13C NMR (CDCl3, 100 MHz): d = 13.0, 14.1, 14.3, 22.6, 23.5, 30.3, 33.6, 36.3, Chem. Eur. J. 2014, 20, 1038 – 1048

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60.6, 115.1, 145.2, 172.7 ppm; HRMS (ESI pos): m/z calcd for C12H23O2 + [M+H] + : 199.1698; found: 199.1701. (E)-Ethyl 4-benzylhex-3-enoate (4 h) was prepared according to procedure A and then warmed to room temperature before hydrolysis: Eluent (hexanes/Et2O 95:5); yield: 42 % (colorless oil); Rf = 0.31 (hexanes/Et2O 95:5); 1H NMR (CDCl3, 400 MHz): d = 0.97 (t, J = 7.6 Hz, 3 H), 1.30 (t, J = 7.1 Hz, 3 H), 2.01 (q, J = 7.6 Hz, 2 H), 3.12 (d, J = 7.3 Hz, 2 H), 4.00 (s, 2 H), 4.18 (q, J = 7.2 Hz, 2 H), 5.43 (t, J = 7.3 Hz, 1 H), 7.21–7.24 (m, 3 H), 7.29–7.33 ppm (m, 2 H); 13C NMR (CDCl3, 100 MHz): d = 12.9, 14.4, 23.0, 33.7, 43.2, 60.7, 117.8, 126.2, 128.4, 129.1, 140.0, 144.2, 172.4 ppm; HRMS (ESI pos): m/z calcd. for C15H21O2 + [M+H] + : 233.1542; found: 233.1530. (2-Hexylcycloprop-2-en-1-yl)methyl diisopropylcarbamate (7 a) was prepared according to procedure A (yield: 63 %), procedure C (yield: 60 %) or procedure D (yield: 56 %): Eluent (hexanes/ EtOAc 90:10); (yellowish oil). Rf = 0.44 (hexanes/EtOAc 90:10); 1 H NMR (CDCl3, 400 MHz): d = 0.15 (t, J = 4.9 Hz, 1 H), 0.50 (dd, J = 8.7, 4.5 Hz, 1 H), 0.87 (t, J = 6.9 Hz, 3 H), 0.92–0.96 (m, 2 H), 1.07 (s, 3 H), 1.20–1.37 (m, 23 H), 3.77 (dd, J = 11.4, 9.6 Hz, 1 H), 4.08 (br s., 2 H), 4.33 ppm (dd, J = 11.4, 6.3 Hz, 1 H); 13C NMR (CDCl3, 100 MHz): d = 14.2, 17.5, 18.1, 20.3, 21.2 (br s.), 22.4, 22.8, 27.0, 29.7, 32.1, 41.3, 45.7 (br s.), 66.1, 156.2 ppm; HRMS (ESI pos): m/z calcd for C18H35NO2 + [M+H] + : 298.2746; found: 298.2794. [(1S*,2S*)-2-Methyl-2-propylcyclopropyl]methyl diisopropylcarbamate (7b) was prepared according to procedure A (yield: 65 %) or procedure D (yield: 66 %): Eluent (hexanes/EtOAc 90:10); (yellowish oil). Rf = 0.46 (hexanes/EtOAc 90:10); 1H NMR (CDCl3, 400 MHz): d = 0.14 (t, J = 4.8 Hz, 1 H), 0.50 (dd, J = 8.7, 4.7 Hz, 1 H), 0.88 (t, J = 7.0 Hz, 3 H), 0.91–0.98 (m, 2 H), 1.07 (s, 3 H), 1.18–1.43 (m, 16 H), 3.79 (dd, J = 11.5, 9.6 Hz, 1 H), 3.90–4.20 (m, 2 H), 4.33 ppm (dd, J = 11.5, 6.3 Hz, 1 H); 13C NMR (CDCl3, 100 MHz): d = 14.4, 17.4, 18.0, 20.0, 20.1, 21.1 (br s.), 22.4, 43.5, 45.9 (br s.), 66.1, 156.2 ppm; HRMS (ESI pos): m/z calcd for C15H29NO2 + [M+H] + : 256.2277; found: 256.2275. [(1S*,2S*)-2-Hexyl-2-methyl-1-phenylcyclopropyl]methyl acetate (7 c) was prepared according to procedure D: Eluent (hexanes/ EtOAc 90:10); yield: 59 % (yellowish oil); Rf = 0.57 (hexanes/EtOAc 90:10); 1H NMR (CDCl3, 300 MHz): d = 0.56–0.65 (m, 1 H), 0.74 (d, J = 4.9 Hz, 1 H), 0.81 (t, J = 7.0 Hz, 3 H), 0.97 (d, J = 4.9 Hz, 1 H), 1.01– 1.22 (m, 8 H), 1.27 (s, 3 H), 1.31–1.48 (m, 1 H), 1.98 (s, 3 H), 4.26 (d, J = 11.5 Hz, 1 H), 4.31 (d, J = 11.5 Hz, 1 H), 7.16–7.30 ppm (m, 5 H); 13 C NMR (CDCl3, 100 MHz): d = 14.1, 18.6, 21.0, 22.6, 23.4, 26.0, 26.7, 29.5, 31.9, 34.3, 37.5, 70.8, 126.4, 128.0, 130.2, 141.6, 171.1 ppm. HRMS (ESI pos): m/z calcd for C19H28O2Na + [M+Na] + : 311.1987; found: 311.1985. [(1S*,2S*)-2-Methyl-1-phenyl-2-propylcyclopropyl]methyl acetate (7 d) was prepared according to procedure D: Eluent (hexanes/ EtOAc 90:10); yield: 63 % (yellowish oil); Rf = 0.56 (hexanes/EtOAc 90:10); 1H NMR (CDCl3, 300 MHz): d = 0.46–0.62 (m, 1 H), 0.70 (t, J = 7.1 Hz, 3 H), 0.74 (d, J = 5.3 Hz, 1 H), 0.96 (d, J = 5.0 Hz, 1 H), 1.12– 1.23 (m, 2 H), 1.25 (s, 3 H), 1.38–1.49 (m, 1 H), 1.97 (s, 3 H), 4.24 (d, J = 11.5 Hz, 1 H), 4.29 (d, J = 11.5 Hz, 1 H), 7.17–7.28 ppm (m, 5 H); 13 C NMR (CDCl3, 100 MHz): d = 14.4, 18.5, 20.0, 21.1, 23.5, 25.9, 34.2, 39.7, 70.9, 126.5, 128.0, 130.3, 141.6, 171.3 ppm; HRMS (ESI pos): m/z calcd for C16H22O2Na + [M+Na] + : 269.1517; found: 269.1517.

Acknowledgements This research was supported by grants from the German–Israel Project Cooperation (DIP) and by the Israel Academy of Sciences and Humanities (140/12). H.E. thanks the Volontariat Inter-

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Full Paper national Program of the French Embassy, G.E. thanks the Israeli Ministry of Foreign Affairs and the WBI (Wallonie Bruxelles International) for funding. The authors thank Lea Sebag for her help. I.M. is holder of the Sir Michael and Lady Sobell Academic Chair. Keywords: carbometalation · chelation cyclopropene · diastereodivergence

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