Dirhodium‐Catalyzed Enantioselective Synthesis of Difluoromethylated Cyclopropanes via Enyne Cycloisomerization

Abstract (Difluoromethylated cyclopropane represents an important motif, which is widely found in bioactive and functional molecules. Despite significant progress in modern chemistry, the atom‐economic and enantioselective synthesis of difluoromethylated cyclopropanes is still challenging. Herein, an Rh2(II)‐catalyzed asymmetric enyne cycloisomerization is described to construct chiral difluoromethylated cyclopropane derivatives with up to 99% yield and 99% ee in low catalyst loading (0.2 mol%), which can be easily transformed into highly functionalized difluoromethylated cyclopropanes with vicinal all‐carbon quaternary stereocenters by ozonolysis. Mechanistic studies and the crystal structures of alkyne‐dirhodium complexes reveal that the cooperative weak hydrogen bondings between the substrates and the dirhodium catalyst may play key roles in this reaction.)


Introduction
Fluorinated cyclopropyl motifs constitute attractive synthons in various bioactive and functional molecules as they combine the conformational rigidity of three-membered rings with the unique and often highly beneficial feature of the fluorinated substituent. [1]In particular, the trifluoromethylated [2] and difluoromethylated [3] cyclopropyl motifs are the most prominent, Scheme 1. Synthetic approaches toward difluoromethylated cyclopropanes.
synthesis of difluoromethylated cyclopropane is still highly desirable.
In the past decades, the transition metal-catalyzed enyne cycloisomerization reaction has evolved as a powerful and convenient strategy for the rapid assembly of carbocyclic and heterocyclic compounds from relatively simple acyclic substrates. [16]n particular, this strategy has been widely used in the construction of cyclopropane-fused polycyclic skeletons in an economical manner, [16a,17] which is distinguished from traditional diazo-based strategy. [18]However, to the best of our knowledge, there is no report on constructing chiral difluoromethylated cyclopropanes using this method.Until recently, we developed a Rh 2 (II)-catalyzed asymmetric cycloisomerization reactions of benzo-fused CF 2 H-substituted enynes, [19] in which the dirhodium-carbene-involved cascaded cyclopropanations occurred, giving the enantioenriched CF 2 H-substituted biscyclopropane products.Inspired by the above results and our previous studies on alkyne-involved carbene chemistry, [20] we envisioned that if a tethered rather than benzo-fused difluoromethylsubstituted enyne was used as substrate, it might undergo the cascaded enyne cycloisomerization and [1,2]-H shift to give difluoromethylated vinylcyclopropane, which can be easily further transformed into highly functionalized difluoromethylated cyclopropane via the oxidative cleavage of the alkenyl (Scheme 1c).
Here we describe the realization of such an Rh 2 (II)-catalyzed intramolecular cycloisomerization of CF 2 H-substituted enynes followed by ozonolysis, allowing the efficient and practical synthesis of a range of tetrahydropyridine-or dihydropyran-fused difluoromethylated cyclopropanes and highly functionalized difluoromethylated cyclopropyl motifs with vicinal all-carbon quater-nary stereocenters in good yields and excellent stereoselectivities.Moreover, X-ray crystal structures of dirhodium-alkyne complexes were obtained successfully to elucidate the possible reaction mechanism.
With the establishment of an efficient route to synthesize the enantioenriched difluoromethylated fused-cyclopropane products 2, we were eager to know whether a collection of simple difluoromethylated cyclopropanes could be synthesized to meet the needs of diverse synthesis.With this in mind, we then searched for the subsequent ring-opening conditions to transform 2 into highly functionalized difluoromethylated cyclopropanes 3. Gratifyingly, as shown in Scheme 3, the electron-rich C═C double bond of the bicyclic compounds 2 could be selectively cleaved through ozonolysis followed by in situ reduction with NaBH 4 to give highly functionalized CF 2 H-substituted cyclopropanes containing vicinal all-carbon quaternary stereocenters.It is worth mentioning that the functional groups of 3, such as amide and hydroxy groups, could serve as useful handles for further manipulations.Then, the versatility of this reaction was tested and the representative examples were listed in Scheme 3a.The variations of R 3 (H, alkyl, aryl) group in product 2 were investigated, which led to the desired CF 2 H-substituted cyclopropane product 3 in moderate to good yields with retention of chiral integrity.8b,13b,15] Additionally, the C═C double bond of 2l could undergo allylation by treatment with allyltrimethylsilane in the presence of trifluoroacetic acid, giving the allylation product 4 in 89% yield and 96% ee.Interestingly, the reaction of 2l with NIS and TMSN 3 in an ice bath overnight generated the difunctionalized product 5 in 62% yield and 94% ee.Finally, the C═C double bond in 2l could also be reduced to give cyclopropane-fused piperidine 6 (92%, 95% ee) under the reduction of Et 3 SiH.
To gain further insights into this asymmetric cycloisomerization reaction, three stable Rh 2 (OPiv) 4 -complexes A-C were obtained as shown in Scheme 4a. [19]Scrutiny of the crystal data of these alkyne-dirhodium(II) -complexes show that a molecule of Rh 2 (II) catalyst was coordinated axially with two alkyne molecules.In complex A and complex B, the coordinated alkynes point toward the opposite directions, while in complex C toward the same directions.Moreover, there are close contacts between the carboxylate oxygen of the catalyst and the substrates 1aj-1al, indicating cooperative weak hydrogen bondings (C−H…O < 2.72 Å) between the substrates (NCH 2 /CF 2 H/CFH 2 ) and the carboxyl ligands of the Rh 2 (II) catalyst (Scheme 4a), which could partially explain why the dirhodium(II) as weak alkynophilic catalyst can activate the carbon-carbon triple bond.As shown in Scheme 4b, the bond angles related to the Scheme 2. Scope of the asymmetric cyclopropanation.e] Rh 2 (S-TCPTTL) 4 (1 mol%); [f ] Rh 2 (S-BTPCP) 4 (2 mol%), 100 °C.Scheme 3. Synthetic applications of products.
hydrogen bondings range from 102.39 o -123.62 o (bond lengths range from 2.379-2.708Å), indicating that these are weak hydrogen bondings. [22]These unique weak hydrogen bondings might also be the reason for the successful isolation of these weakly coordinated complexes.In addition, Rh 2 (OPiv) 4 -complexes A-C were fully characterized by NMR spectroscopy.There are slightly downfield shifts for the atoms on terminal groups (CF 2 H, CFH 2 , H) and -position of alkyne-Rh complexes in the 1 H NMR and 13 C NMR spectra.Importantly, the 13 C signals of the alkynes (,  position) in complexes A-C were shifted to a higher frequency because of the feedback effect of the rhodium. [23]These NMR data support the existence of weak hydrogen bondings and coordination interactions between the dirhodium catalysts and the alkyne substrates 1aj-1al in solution.As a result, the enynes 1am and 1an which correspond to 1ak and 1al were subjected to the reaction, giving the target products 2am (93%, 89% ee) and 2an (84%, 43% ee), although an elevated temperature was required for the formation of 2an (Scheme 4c).These experimental results are consistent with the crystallographic and spectral data.However, when replacing the capping group of the C≡C with the neutral -CH 3 group or the electron-deficient -CF 3, -COAr groups, no desired products were observed even at elevated temperature, which could be attributed to the increasing steric bulk.In addition, 1a and the deuterated counterparts 1aq were subjected to the one-pot competitive kinetic isotope effect (KIE) experiment and the parallel KIE experiment, the k H /k D are 1.19 and 1.16, respectively.That's to say, when -CF 2 H was replaced by -CF 2 D, a slower reaction rate was observed because of the weaker hydrogen bondings between the substrate and the dirhodium catalyst (Scheme 4d).These results also suggested the key roles of weak hydrogen bondings in our catalytic system. [24]

Conclusion
In summary, we have developed an efficient method for the synthesis of chiral difluoromethylated cyclopropanes via dirhodiumcatalyzed cycloisomerization of 1, 6-enynes.Moreover, a series of highly functionalized difluoromethylated cyclopropanes with vicinal all-carbon quaternary stereocenters could be obtained through the subsequent ozonolysis process.This protocol features high atom economy, low catalyst loading, good functional group tolerance, and excellent enantioselectivities.Moreover, the cooperative weak hydrogen bondings between the substrates and the dirhodium catalyst were found in single crystal structures of alkyne-dirhodium complexes and NMR experiments.These cooperative weak hydrogen bondings possibly account for the efficient activation of alkyne by a weak alkynophilic dirhodium catalyst, which was consistent with the control experiments.We believe that this method is a significant and valuable alternative in the preparation of enantiomerically enriched difluoromethylated cyclopropane derivatives.

Table 1 .
Optimization of the reaction conditions.
a) The reaction was conducted with 1a (0.05 mmol) in toluene (0.5 mL), RT, under N 2 , 48 h; b) NMR yield; c) The ee was determined by chiral HPLC; d) Isolated yield.