{'fraction_non_alphanumeric': 0.028655683056606193, 'fraction_numerical': 0.01980896211295596, 'mean_word_length': 4.986185725249425, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Diastereodivergent combined carbometalation/zinc homologation/C–C fragmentation reaction as an efficient tool to prepare acyclic allylic quaternary carbon stereocenters† †Electronic supplementary information (ESI) available: Experimental procedures, spectroscopic data and copies of 1H and 13C NMR sp

A new strategy has been developed to construct enantiomerically enriched allylic quaternary carbon stereocenters in a single-pot operation through a combined carbometalation/zinc homologation/fragmentation sequence.


Introduction
In the last few decades, numerous approaches to integrate multiple chemical steps in a single-pot operation 1 have been described, offering reliable and powerful strategies for the synthesis of ne chemicals. 2 In this context, the construction of several carbon-carbon (C-C) bonds with simultaneous control of newly formed asymmetric centers, including the formation of challenging quaternary carbon stereocenters, 3 is of paramount importance for the development of complex molecular frameworks. 4 Particularly interesting would be the formation of such stereocenters adjacent to allylic motifs 4 as these sub-structures are abundant in biomolecules and natural products. 5 Although several excellent and highly selective approaches have been reported for the construction of acyclic allylic carbon quaternary stereocenters, 6-10 it becomes more intricate when the synthesis has to be performed in a single-pot operation. 11 For instance, although copper catalysed asymmetric conjugate addition is probably the most well established transformation (Fig. 1, path A), 12 asymmetric 1,4addition to an extended conjugated system is more challenging as the 1,6-addition product is usually preferred over 1,4-addition ( Fig. 1, path B). 13 A more successful alternative approach to reach the same products is the asymmetric 1,4-addition of vinyl metal species to Michael acceptors. 14 Although methods coupling asymmetric catalysis with fragmentation of strained building blocks have been reported recently, none could be used for the preparation of acyclic allylic carbon quaternary stereocenters. 15 Herein, we would like to report our efforts to address this issue by performing a new tandem approach leading to the formation of two new carbon-carbon bonds in a single-pot operation, including the formation of the desired acyclic allylic quaternary carbon stereocenter (Fig. 1, Path C) from easily accessible starting materials. This combined reaction consists of the diastereoselective carbometalation reaction 16 of enantiomerically enriched substituted cyclopropenyl esters 1, followed by a homologation reaction 17 of the resulting cyclopropyl metal species 2 leading to a cyclopropylmethyl metal 3, which subsequently undergoes a carbon-carbon bond cleavage 18 to give the enantiomerically enriched acyclic allylic quaternary carbon stereocenter 4 as described in Fig. 1, path C. Although this proposed sequence is very appealing, the unique formation of the linear product 4 directly from 1, promoted by a combination of organometallic species in high chemical yield and with a high enantiomeric ratio, requires a cascade of high-yielding events with perfect control of all the elementary steps. It should be noted that the enantiomerically enriched cyclopropenyl ester starting materials 1 are readily accessible through the asymmetric metalcatalyzed decomposition of diazoesters with alkynes. 19 The enantiomeric ratio of the acyclic allylic quaternary stereocenter in 4 results from the diastereoselectivity of the carbometalation reaction.

Results and discussion
We started our research by investigating the diastereoselectivity of the carbometalation reaction of cyclopropenyl ester 1. In our synthetic plans, the presence of the ester was not only needed to achieve good diastereoselectivity for the carbometalation reaction, but was also a key element for successful ring-fragmentation of the newly formed donor-acceptor cyclopropylmethyl metal species 3. 20 Hence, to address the initial step of this sequence (transformation of 1 into 2), our model cyclopropenyl ester substrate (racemic 1a) was treated with various organocopper species in different solvents as described in Table 1. When 1a was treated at À45 C in THF with 1.05 equivalents of MeCu, easily prepared by mixing MeLi and CuI in a 1 : 1 ratio, the carbometalated product 2a anti was rapidly obtained aer hydrolysis (less than 30 minutes) with a very high anti-diastereoselectivity in good yield (Table 1, entry 1). 21 The conguration of 2a anti was established by NOE experiments (see ESI †). The preferential formation of diastereomer 2a anti can only be possible if the carbometalation reaction is sterically driven. A coordinating solvent such as THF makes the organocopper species less prone to chelation by the ester and therefore it prefers to react on the re-face of the cyclopropene derivative 1a. If the assumption that solvent plays a crucial role in the control of the diastereoselectivity of the carbometalation step is correct, then a less Lewis basic solvent should favour addition on the si-face through coordination of the organometallic species with the ester. Indeed, when a slightly less coordinating solvent such as 2-methyl THF was used, the selectivity towards the formation of 2a anti dropped slightly ( Table 1, entry 2). On further decreasing the Lewis basicity of the solvent ( Table 1, entries 3 to 5, Et 2 O, hexane and toluene respectively), the tendency of the organometallic species to be coordinated by the ester group increases and therefore the isomer 2a syn could be prepared as the unique diastereoisomer (Table 1, entry 5). The relative conguration of 2a syn was established by comparing the NOE and 13 C NMR experiments with 2a anti (see ESI †). The same trend was also found for the addition of organocopper species originating from Grignard reagent (prepared by mixing MeMgBr and CuI in a 1 : 1 ratio), and although the formation of the anti-addition product 2a anti in THF was less diastereoselective (Table 1, compare entries 1 and 6), it was still excellent for the formation of the syn-diastereoisomer 2a syn (Table 1, entry 8). It should be noted that diastereoselective carbometalation of cyclopropenyl esters such as 1a has already been described, but it was always achieved through variation of the organometallic species and never by simple variation of the solvent for a given organocopper entity. 16 Having access to both syn and anti diastereoisomers of the carbometalated products at will according to the nature of the solvent, we then turned our attention to the zinc homologation reaction of the racemic cyclopropyl copper species 2Cu anti originating from the carbometalation reaction of MeCu in THF (MeCu was formed from MeLi and CuI as described in Table 1, entry 1). For this purpose, CH 2 I 2 and Et 2 Zn in a 1 : 1 ratio were added to the reaction mixture at À45 C, and upon warming to À20 C, within 2 hours, the homologated cyclopropylmethyl zinc derivative 22 3 gave 4a as described in Fig. 2. Indeed, as cyclopropylcopper 2Cu anti does not react with CH 2 I 2 , the reaction between Et 2 Zn and CH 2 I 2 occurs rst leading to the in situ formation of the zinc carbenoid ICH 2 ZnEt. 23 Then, 2Cu anti is homologated by the zinc carbenoid to generate the in situ reactive cyclopropylmethyl zinc (or copper) derivative 3 (see Fig. 1), which instantaneously undergoes a C-C bond fragmentation. 24 Although the combined carbometalation/zinc homologation/fragmentation reaction proceeded smoothly according to our original plan to give 4a, the conversion of 2Cu anti into 4a was only moderate (2a anti /4a ¼ 27/73 aer hydrolysis). To improve the conversion, it was then anticipated that increasing the nucleophilicity of the carbon atom bearing the organocopper species should increase its reactivity towards the ambiphilic zinc carbenoid species EtZnCH 2 I.
To this end, various donor ligands were added to the reaction mixture to improve the reactivity of the cyclopropyl copper species (see ligands in Fig. 2). 25 Indeed, we were pleased to observe that the addition of TMEDA (L 1 ) or 2-2 0 -bipyridine (L 2 ) as ligand improved the conversion of the desired product 4a (2a anti /4a ¼ 12/88 and 13/87 respectively aer hydrolysis).    The best conversion could be reached when phenanthroline (L 3 ) was added to 2Cu anti , as the ratio became excellent (2a anti /4a ¼ 6/94 aer hydrolysis) and the nal product 4a could be isolated in 72% yield. This sequence of carbocupration/zinc homologation/C-C bond cleavage has been generalized to different functionalized substrates (see scope in Fig. 2) and in all cases, the reactions proceed smoothly for the one-pot transformation of 1 into 4.
Both cyclopropenyl esters (-OEt and -OBn) undergo this combined transformation (compare 4b to 4c, 4d to 4e and 4f to 4g in Fig. 2), but it should be noted that the products resulting from the reaction with the benzyl ester (4b, 4d, 4g) are easier to purify by column chromatography from the remaining carbometalated products aer hydrolysis (2 anti ) than the products possessing the ethyl ester (4c, 4e, 4f). These combined reactions are not restricted to the introduction of a methyl group, as various other alkyl groups could be added in good yields by simply changing the nature of the starting organocopper reagent (compare 4b to 4d, 4f to 4h and 4g to 4h, Fig. 2). The reaction of cyclopropenyl ester 1d with phenylcopper also proceeds well, but we were unable to separate the desired product 4m from the carbometalated product 2m anti aer hydrolysis. Similarly, when we treated a vinylcopper derivative (prepared from ethenylmagnesium bromide and CuI in a 1 : 1 ratio), as a representative example of an sp 2 organometallic species, with cyclopropenyl ester 1j, the reaction proceeds smoothly but again, we were unable to separate the desired product 4n from the hydrolysed carbometalated product 2n anti . It is worth mentioning that this sequence of vinyl cupration/ zinc homologation/fragmentation opens new avenues for the preparation of skipped dienes possessing a quaternary carbon stereocenter. Notably, the presence of other functional groups in the original alkyl chain of the cyclopropenyl ester is well tolerated (formation of 4j-l, Fig. 2). Having established an easy protocol for the preparation of racemic 4 from these very simple starting materials, the synthesis of enantiomerically enriched cyclopropenyl esters 1b (R 1 ¼ Ph(CH 2 ) 2 ), 1e (R 1 ¼ PhCH 2 ) and 1f (R 1 ¼ Hex) was easily achieved in good enantiomeric ratio (1b er 96 : 4, 1e er 93 : 7 and 1f er 91 : 9) through cyclopropenation of the terminal alkyne with benzyl diazoacetate and Rh 2 (OAc)(R,R-DPTI) 3 (DPTI ¼ diphenyltriylimidazolidinone) as catalyst. 26 Interestingly, the enantiomeric ratios of these cyclopropenyl benzyl esters are lower than the ones obtained for cyclopropenyl ethyl esters (ethyl diazoacetate generally leads to enantiomeric ratios in the range of 97 : 3), but for the sake of simplicity, we decided to illustrate our concept with starting materials that would require a minimum number of chemical steps. When the sequence of carbocupration, zinc homologation and C-C bond fragmentation was performed on these enantiomerically enriched cyclopropenyl esters, enantioenriched acyclic allylic molecular architectures (4b,g,h,i) possessing a quaternary carbon stereocenter were easily obtained through the creation of two C-C bonds in a single-pot operation. HPLC analyses (see ESI †) show that the chiral information at the carbon atom connected to the ester moiety in 1b,e and f was quantitatively transferred to the nal products 4b (er 96 : 4), 4g and 4h (er 93 : 7) and 4i (er 91 : 1), Fig. 2. It was therefore clear that the quaternary stereocenter was at no risk of epimerization through the whole process, and one could prepare the expected products with the same enantiomeric ratio as in the starting materials.
In contrast to any typical enantioselective synthesis where the independent formation of the two enantiomers of a product can only be achieved by changing the chirality of the ligand (or substrate) associated with the enantioselective transformation, 27 the diastereodivergent carbometalation of 1, controlled by the nature of the solvent as described in Table 1, should therefore lead to the enantiodivergent synthesis of 4 from the same enantiomerically enriched starting material 1 (as summarized in Fig. 3).
Although the best ligand to promote the zinc homologation of 2Cu anti was phenanthroline L 3 , it was unclear that the same ligand would be optimal when the rst step was performed in a non-polar solvent. To reach this new goal, we had to again optimise the reaction sequence for the formation of the desired products 4 from the syn-diastereomer 2Cu syn in the presence of a non-polar solvent (such as toluene, see Table 1, entries 5 and 8). It was rst rapidly found that the zinc homologation for the transformation of 2Cu syn into 4a was more efficient when the initial organocopper species was prepared from an organolithium (R 2 Cu$LiI, Table 1, entry 5) instead of an organomagnesium species (R 2 Cu$MgX 2 , Table 1, entry 7). Aer extensive experiments, we were pleased to nd that the zinc homologation could now be best performed in the presence of a non-nucleophilic potassium tert-butoxide ligand (for all other ligands tested, see ESI †) with addition of THF as co-solvent. It is important to note that the reaction performed under identical conditions but in the absence of the potassium tert-butoxide ligand results in very poor conversion, which underlines the effect of this particular ligand on the nucleophilicity of the metalated carbon center stabilized by the chelating ester. Once the best experimental conditions were in hand, various allylic esters 4 possessing quaternary carbon stereocenters were prepared in a single-pot operation from cyclopropenyl esters 1 as illustrated in Fig. 4.
The scope of this new reaction sequence of syn-diastereoselective carbometalation, zinc homologation and selective C-C bond cleavage is equally good albeit with slightly lower yields for the nal products 4. To illustrate the potential of this diastereodivergent approach, both enantiomers of 4i were prepared from the same cyclopropenyl ester enantiomer 1f (R 1 ¼ Hex, er 91 : 9). When the carbocupration of (S)-1f was performed with MeCu$LiI in THF followed by the subsequent addition of CH 2 I 2 , Et 2 Zn and phenanthroline (L 3 ) as ligand, the selective C-C bond cleavage led to the corresponding allylic (S)-4i with an enantiomeric ratio of 91 : 9 in 65% yield (Fig. 5).
On the other hand, if the same cyclopropenyl ester (S)-1f is added to the organocopper MeCu$LiI in toluene followed by subsequent zinc homologation in the presence of potassium tert-butoxide as ligand, the selective C-C bond cleavage provides the allylic (R)-4i in similar yield (63%) with almost the same enantiomeric ratio (er 90 : 10) (Fig. 5).

Conclusions
A new sequence of diastereoselective carbometalation/zinc homologation/C-C bond cleavage allows the easy transformation of enantiomerically enriched cyclopropenyl esters into acyclic allylic moieties bearing challenging quaternary carbon stereocenters in a single-pot reaction through the formation of two new C-C bonds. As the carbometalation reaction may lead to two different diastereoisomers according to the nature of the solvent, this strategy paves the way to the diastereodivergent synthesis of both enantiomers of 4 at will.