Asymmetric [2+1] cycloaddition of difluoroalkyl-substituted carbenes with alkenes under rhodium catalysis: Synthesis of chiral difluoroalkyl-substituted cyclopropanes

Summary Herein, we report a novel strategy for the synthesis of chiral difluoroalkyl-substituted cyclopropanes through enantioselective [2 + 1] cyclopropanation of alkenes and difluoroalkyl-substituted carbenes under rhodium catalysis, wherein the newly designed α, α-difluoro-β-carbonyl ketone N-triftosylhydrazones are used as the difluoroalkyl-substituted carbenes precursors. This approach represents the first asymmetric cyclopropanation of alkenes with difluoroalkyl carbenes, featuring high yield, high enantioselectivity, and broad substrate scope. Gram-scale synthesis and further interconversion of diverse functional groups demonstrate the usefulness of this protocol in the preparation of diverse functionalized chiral difluoroalkyl-substituted cyclopropanes.


INTRODUCTION
The synthesis of partially fluorinated chiral organic molecules has drawn increasing attention, owing to the applications of such substrates in the design and development of bioactive molecules and drugs. [1][2][3][4] Difluoromethylene carbenes, which can considered as a suitable source of partially fluorinated moieties, have been widely used for the introduction of difluoroalkyl units into molecular skeletons. [5][6][7][8][9] However, in sharp contrast to the significant advances in the asymmetric reaction of perfluoroalkyl carbenes, 5-18 the study on the enantioselective reactions involving difluoromethylene carbenes is still in its very early stage. To date, only three types of reactions are known in the prior art, namely the enantioselective cyclopropenation and aziridination reactions developed by Ma and coworkers 19,20 and our report of the asymmetric intramolecular C-H insertion of ethers (Scheme 1A). 21 The [2 + 1] cyclopropanation represents one of the most typical reactions of carbenes; however, the analogous asymmetric reaction involving difluoroalkyl-substituted carbenes, which would allow for the synthesis of chiral difluoroalkyl-substituted cyclopropanes that have been found as the key structural unit of HIV inhibitors, remains undeveloped so far. 22,23 This may be due to the low reactivity of the available difluoroalkyl-substituted carbenes and to the lack of appropriate carbene precursors. Regarding the synthesis of chiral difluoroalkyl cyclopropanes, only one strategy has been disclosed, which involves the cycloaddition of difluoromethyl olefins with diazo compounds under, respectively, rhodium and enzyme catalysis. 24,25 On the other hand, the direct handling of hazardous diazo reagents remains until now the main disadvantage of this strategy. Consequently, an alternative strategy for asymmetric cyclopropanation of alkenes using difluoroalkyl-substituted carbenes is highly desirable.
As our continued interest in the chemistry of fluoroalkyl N-triftosylhydrazones, [26][27][28][29][30] herein, we report the first enantioselective cyclopropanation of alkenes with difluoroalkyl-substituted carbenes in situ generated from a, a-difluoro-b-carbonyl ketone, which enables the successful application of difluoromethylene carbene in the asymmetric cyclopropanation. The use of N-triftosylhydrazones as difluoroalkyl-substituted carbenes surrogates avoids the need for direct manipulation of hazardous diazo reagents and, thus, reduces safety issues. It is worth mentioning that diverse alkenes, including aryl-alkyl, diaryl, and aryl terminal alkenes, are suitable in this protocol and have been proved to provide the chiral cyclopropanes in high yield and excellent enantioselectivity. [31][32][33] More importantly, N-triftosylhydrazones, with the advantage of easy decomposition at relatively low temperature, plays an essential role in the success of this kind of novel asymmetric [2 + 1] cycloaddition reaction. Experimental outcome has shown that the Rh 2 (S-PTAD) 4 catalyst has a highly stereo-selectivity for this asymmetric [2 + 1] cycloaddition process. To better understand the origin for the stereo-selectivity, a plausible mechanism was proposed using the cycloaddition of N-triftosylhydrazone 1, which could be decomposed in situ to form the diazo compound under alkaline conditions, 41 with 1,1-diphenylethylene as model and rationalized by density functional theory calculations at M06L/6-31G(d)-SDD(Rh) level of theory (for detailed computational methods, see Supplemental information). As shown in Scheme 4, the cycloaddition process is stepwisely owing to the geometric constraints derived from the body cavity of rhodium carbene. Firstly, the nucleophilic attack of 1,1-diphenylethylene to the carbene carbon can occur separately from the Sior Re-plane of the carbene carbon, which determines the stereoselectivity of the product (DG s (Si-TS1) = 14.0 kcal/mol; DG s (Re-TS1) = 25.1 kcal/mol) (Scheme 4A). The non-covalent interactions analysis (Scheme 4B) shows that Si-TS1 displayed stronger hydrogen bond interactions (C-H$$$F, C-H$$$O) than Re-TS1, resulting in a more stable transition state and thus a lower kinetic energy barrier. Subsequently, the cyclization process from Si-int1 and Re-int1 to form the final enantioselective product via Si-TS2 (DG s = 3.3 kcal/mol) and Re-TS2 (DG s = 16.3 kcal/mol) occurred. The lower energy barrier for Si-TS2 may be derived from the more and stronger interactions exist in the configuration (See the part circled in red; Scheme 4C, upside), which renders the transition state more stable. Therefore, the formation of Si-pro is both kinetically and thermodynamically more favorable than Re-pro; this is in consistence with the experimental outcomes.
In summary, we have reported the first asymmetric [2 + 1] cycloaddition reaction of alkenes with difluoroalkyl-substituted carbenes, which were generated in situ from the easily decomposable a,a-difluorob-carbonyl ketone N-triftosylhydrazones. This protocol enables the enantioselective cyclopropanation of difluoroalkyl-substituted carbenes with alkenes, thereby providing a facile route to access enantioenriched difluoroalkyl-substituted cyclopropanes in high yield and excellent enantioselectivity. No doubt that the a, a-difluoro-b-carbonyl ketone N-triftosylhydrazones as the difluoroalkyl-substituted carbenes surrogates would find wide applications in asymmetric difluoroalkyl carbene transfer reactions in the near future.

Limitations of the study
This study is limited to the terminal alkenes, and it is still necessary to further develop an asymmetric catalytic system suitable for internally substituted alkenes.

STAR+METHODS
Detailed methods are provided in the online version of this paper and include the following: iScience Article

Materials availability
This study did not generate new unique reagents.
All reagents were purchased from commercial sources (Energy Chemical, Adamas-betaâ, J&K Scientific, Sigma-Aldrich) and used without purification unless otherwise mentioned. The products were purified by column chromatography over silica gel (200-400 size). 1  d Any additional information required to reanalyze the data reported in this paper can be obtained from the lead contact upon request.

METHOD DETAILS
General procedure for the asymmetric cyclopropanation In a nitrogen-filled glovebox, a flame-dried screw-cap reaction tube equipped with a Teflon-coated magnetic stir bar was charged with sulfonyl hydrazone 1 (0.8 mmol) and anhydrous TFT solvent (1.0 mL). The reaction mixture was stirred until complete dissolve, DIPEA (0.8 mmol) was added to the reaction system. The alkene 2 (0.4 mmol) was dissolved in 1.0 mL of anhydrous TFT and added to the reaction system. Rh 2 (S-PTAD) 4 (0.5 mol%) was dissolved in anhydrous TFT (1 mL) and then added to the reaction system. The mixture was stirred at 25 C for 12 h until the reaction was complete as indicated by 1 H NMR. The reaction crude was filtered through a short silica gel eluting with DCM. The filtrate was evaporated under reduced pressure to leave a crude mixture, which was separated by flash column chromatography to afford the pure product.
Note: The yield of the reaction decreases as the dosage of DIPEA decreases, but the enantioselectivity remains unchanged. iScience Article Synthesis of racemate: The same procedure uses Rh 2 (esp) 2 instead of Rh 2 (S-PTAD) 4 and performs at room temperature.
General procedure for the synthesis of olefins A sealed flask was charged with benzaldehyde (10 mmol), then THF (30 mL) was added and stirred at 0 C. Grignard reagent (15 mmol) was slowly added and the mixture was placed at room temperature for 4 h. When the reaction was complete (monitored by TLC), saturated NH 4 Cl was added. The mixture was extracted with EA (30 mL 3 3), then the organic phase was dried with anhydrous Na 2 SO 4 , concentrated under reduced pressure to give the pure compound.

Synthesis of benzophenones
A round-bottomed flask was charged with alcohol and dissolved in DCM (40 mL). Then Dess-Martin oxidant (1.5 equiv) was slowly added and stirred at room temperature overnight. After completion of the reaction (monitored by TLC), saturated NaHCO 3 and Na 2 S 2 O 3 solution were slowly added. Extracted with DCM (30 mL 3 3) and washed the organic phases with brine, then dried with anhydrous Na 2 SO 4 . The residue was purified by flash column chromatography to give the corresponding benzophenone compound.

Synthesis of olefins
A sealed flask was charged with methyltriphenylphosphine bromide (1.5 equiv), THF (30 mL) was added and stirred at 0 C. Potassium tert-butoxide (1.5 equiv) and ketone (1.0 equiv) in THF (20 mL) was slowly added, the mixture was reacted at room temperature for 4 h. After completion of the reaction (monitored by TLC), NH 4 Cl solution was slowly added. The mixture was extracted with EA (30 mL 3 3) and dried with anhydrous Na 2 SO 4 . Then concentrated under reduced pressure to give the pure compound.perform flash column chromatography.
General procedure for the synthesis of compound 47 A sealed reaction tube was charged with 24 (0.2 mmol) and ammonia (7 M in methanol) (0.5 mL). The mixture was stirred at 25 C for 16 h. Then the mixture was concentrated under reduced pressure to give the pure compound.
General procedure for the synthesis of compound 48 A sealed reaction tube was charged with LiAlH 4 (0.3 mmol) under nitrogen atmosphere. 24 (0.2 mmol) in THF (3.0 mL) was added to the reaction tube under 0 C. Then the mixture was stirred at 25 C for 4 h. After the reaction was complete (monitored by TLC), aqueous NH 4 Cl was added, and quenched with EA. The organic phase was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to give the pure compound.
General procedure for the synthesis of compound 49 A bottom flask was charged with 24 (0.2 mmol), NaOH (0.4 mmol) and EtOH (2.0 mL). The mixture was stirred at 60 C for 2 h. After the reaction was complete (monitored by TLC), aqueous NH 4 Cl was added, and quenched with EA. The organic phase was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to give the pure compound.
General procedure for the synthesis of compound 50 A sealed reaction tube was replaced nitrogen three times, then 24 (0.2 mmol) in dry THF (3.0 mL) was added. The mixture was placed at À78 C, n BuLi (1.6 M in hexane, 0.25 mmol) was added dropwise and stirred for 2.5 h. After the reaction was complete, aqueous NH 4 Cl was added, and quenched with CH 3 CO 2 Et. The organic phase was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure and purified by column chromatography to give the pure compound.