Dynamic Catalytic Highly Enantioselective 1,3‐Dipolar Cycloadditions

Abstract In dynamic covalent chemistry, reactions follow a thermodynamically controlled pathway through equilibria. Reversible covalent‐bond formation and breaking in a dynamic process enables the interconversion of products formed under kinetic control to thermodynamically more stable isomers. Notably, enantioselective catalysis of dynamic transformations has not been reported and applied in complex molecule synthesis. We describe the discovery of dynamic covalent enantioselective metal‐complex‐catalyzed 1,3‐dipolar cycloaddition reactions. We have developed a stereodivergent tandem synthesis of structurally and stereochemically complex molecules that generates eight stereocenters with high diastereo‐ and enantioselectivity through asymmetric reversible bond formation in a dynamic process in two consecutive Ag‐catalyzed 1,3‐dipolar cycloadditions of azomethine ylides with electron‐poor olefins. Time‐dependent reversible dynamic covalent‐bond formation gives enantiodivergent and diastereodivergent access to structurally complex double cycloadducts with high selectivity from a common set of reagents.


Introduction
Thes ynthesis of organic compounds is dominated by kinetically controlled reactions,w hich enables irreversible formation of strong covalent bonds. [1,2] Thei rreversible nature of the reaction guarantees that, once the particular product is formed, it is stable and will not be reformed or converted into another product. [1] As an alternative to selective product formation, Rowan et al. introduced the concept of dynamic covalent chemistry (DCC). [2] In DCC covalent bonds can be formed and broken reversibly in afast equilibrium and under conditions in which equilibrium control leads to efficient formation of products under thermodynamic control. [2] DCC has been proposed primarily in the context of supramolecular chemistry including applications in combinatorial chemistry. [3,4] Thereversible nature of reactions permits "error checking" and "proof reading" for interconverting components to access the thermodynamically most stable adduct. [4][5][6][7] However,w hile in supramolecular chemistry weak noncovalent interactions dominate,for DCC more robust covalent bonds are relevant with slower kinetics of bond cleavage and formation. In DCC the relative stability of the products (i.e., thermodynamic parameters) determines the product distribution rather than the relative magnitudes of energy barriers of each pathway (i.e., kinetic parameters) (Scheme 1a). Since both the thermodynamic and the kinetic parameters are functions of reaction parameters,t he outcome is highly dependent on reaction conditions such as temperature,catalyst and reaction time required to reach an equilibrium. [7,8] Tu rner et al. employed DCC in enzyme catalysis.T hey used an aldolase for preparation of ad ynamic combinatorial library through stereoselective carbon-carbon bond formation and enabled change in equilibrium in product distribution in presence of athermodynamic trap. [9] DCC was also observed for non-enzymatic aldol/retroaldol reactions, [5,10] for Diels-Alder cycloadditions at higher temperature, [11] and for additional transformations including Michael additions, [12] alkene cross-metathesis. [13] and [2+ +2] cycloaddition. [14] However,n on-enzymatic enantioselective catalysis of DCC has not been reported and DCC has not been observed for dipolar cycloadditions yet. Herein we describe the discovery of catalytic and highly enantioselective dynamic covalent chemistry in metal complex-catalyzed 1,3dipolar cycloaddition reactions,that is,areaction type which belongs to the most important and widely used transformation in organic synthesis.

Results and Discussion
To establish the reaction sequence initial screening studies were conducted with cyclic enone (R = H) and glycine methyl ester imine 2a in dichloromethane in the presence of base (Scheme 1b,S upplementary Table 1). We found that the double 1,3-dipolar cycloaddition can be catalyzed efficiently with AgOAc to yield cycloadduct rac-3 a with 82 %yield and high diastereoselectivity (d.r. > 20:1). Ther egioselectivity of the first addition was investigated by treating cyclic enone (R = H) with 1.1 equiv of imine 2a under the same reaction conditions which resulted in the regioselective formation of rac-4 a with high diastereoselectivity (> 20:1) in 72 %y ield (Scheme 1b). Achange in regioselectivity was observed when amethyl substituent was introduced at the endocyclicdouble bond of the dipolarophile (R = CH 3 ). Monocycloaddition of cyclic enone and the ylide derived from glycine methyl ester imine 2a resulted in formation of spirocycle rac-4 b in 57 % yield and with good diastereoselectivity (10:1). Thep roduct rac-4 a reacts with glycine methyl ester imine 2a to form rac-3a with high diastereoselectivity (> 20:1) and 75 %y ield under the same reaction conditions.
In order to explore the enantioselective synthesis of tricyclic compound 3a,d ifferent chiral ligands,m etal catalysts,b ases and solvents were investigated (Supplementary Table 2). Optimization experiments indicated that the best result could be obtained using AgOAc (6 mol %) as aL ewis acid in combination with the S,P-ferrocenyl ligand (R)-Fesulphos,( L1 6.5 mol %) in dichloromethane using cesium carbonate (Cs 2 CO 3 ;40mol %) as abase at room temperature after 24 h. Under these conditions,tricyclic compound 3a was obtained in 81 %y ield with high diastereoselectivity (d.r. > 20:1) and excellent enantioselectivity (99 % ee;T able 1). Notably,t his reaction created eight stereocenters including one quaternary center in ao ne-pot transformation. The absolute configuration of product 3awas determined by crystal structure analysis (Supporting Information, Crystal Data), which revealed that product 3a is formed by double endo-selective cycloaddition.
Thes cope of the tandem reaction is wide.R egardless of the substitution pattern of the aromatic ring, enones 1 react with various azomethine ylides derived from imines 2 with moderate to good yields of 40-81 %w ith high diastereo-(> 20:1) and enantioselectivity (91-99 % ee, 3a-3y in Table 1). In the presence of electrondonating substituents such as methyl-or methoxy groups (3e and 3g,r espectively), the yield was reduced to 60-63 %w hereas electron-neutral or -withdrawing substituents such as bromine or fluorine (3a and 3f)l ed to higher yields.Heterocycle-containing azomethine ylides reacted to provide products (3i and 3j)i nm oderate yield and with high enantioselectivity (95 % ee). In general, the enantioselectivity of the double cycloaddition remained consistent regardless of substitution pattern. When an enone with as terically hindering tert-butyl substituent on the exocyclicolefin was employed, the double cycloaddition product (3v)w as obtained in 21 %y ield, and high enantioselectivity was still observed (93 % ee). Furthermore, introduction of am ethyl substituent to the endocyclic double bond of the enone yielded 3x with two quaternary centers with high enantioselectivity (93 % ee).
Amore hindered a-phenyl substituted ylide,a fforded product 3k in 21 %y ield but with high enantioselectivity (91 % ee), thereby inducing formation of three quaternary centers.For all of examples shown in Table 1, the products were formed as single diastereomers (d.r. > 20/1) after 24 h.
To rapidly expand the chemical space accessible via the double cycloaddition, we explored whether as equential multicomponent transformation could give access to cycloadducts formed from two different imines.F ollowing optimization, as equence was established in which cyclic  enones 1 were treated with 1.1 equiv of an iminoester 2 in the presence of (R)-Fesulphos (L1,6 .5 mol %), AgOAc (6 mol %) and Cs 2 CO 3 (40 mol %) in dichloromethane for 3h (Supplementary Methods,p rocedure B) followed by treatment with as econd, different iminoester 2' ' for 24 h. Based on the different reactivity of the double bonds,the first cycloaddition occurs with the endocyclic double and the second cycloaddition targets the exocyclic double bond, which results in selective formation of mixed double cycloaddition products 5 by means of as equential one-pot, threecomponent reaction (5a-5j in Table 2). Them ixed double cycloaddition products 5 were obtained with high diastereoselectivity but, unexpectedly,w ith lower enantioselectivity (82-91 % ee)r elative to the two-component double-cycloaddition products 3,for which the products were formed with up to 99 % ee.
To explain the findings we hypothesized that both cycloadditions,that is,formation of 3 and 4,may be the result of an enantioselectively catalyzed dynamic covalent process.Inthis process the double cycloaddition first proceeds reversibly through ak inetically controlled pathway due to the lower energy barrier of the transition state followed by an interconversion to the thermodynamically more stable product by af ast equilibrium process.T ov alidate this mechanistic hypothesis changes in enantioselectivity of the double cycloaddition were investigated stepwise ( Table 3, Table 5). Upon treatment of cyclic enone 1a with 1.1 equiv of iminoester 2a in the presence of (R)-Fesulphos L1 (6.5 mol %), AgOAc (6 mol %) and Cs 2 CO 3 (40 mol %) in DCM, monoadduct 4a can be formed with varying enantioselectivity in the range of 70-95 % ee (Table 3, Supporting Information, Experimental studies). Thel ower and varying enantioselectivity for formation of monoadduct 4a in comparison to double cycloaddition product 3a (99 % ee,T able 1) indicates that, indeed, enantioselective retro-cycloaddition catalyzed by the Ag/(R)-Fesulphos complex may occur, which changes the enantiomeric ratio during the reaction. Thed ecrease in enantioselectivity for formation of monoadduct 4a is even more obvious when the ratio of AgOAc and (R)-Fesulphos is changed (Table 3). Tr eatment of cyclic enone 1a with 1.1 equiv of iminoester 2a in the presence of 12 mol % instead of 6.5 mol %(R)-Fesulphos L1, AgOAc (6 mol %) and Cs 2 CO 3 (40 mol %) in DCM, leads to formation of monoadduct 4a with 90-95 % ee after 3h but with only 80 % ee after 16 h ( Table 3, Supporting Information, Experimental studies).
Cycloaddition product 3a is formed with 99 % ee regardless of the AgOAc/(R)-Fesulphos ratio.These results indicate that one enantiomer of monoadduct 4a is involved in aretrocycloaddition as it matches with the chiral environment of the Ag/(R)-Fesulphos complex in as elective manner.I n order to confirm that retrocycloaddition is an enantioselective process,e nantioenriched mono adduct 4a (81 % ee)w as subjected to reaction with (R)-Fesulphos L1 (12 mol %), AgOAc (6 mol %) and Cs 2 CO 3 (40 mol %) in DCM and ad ecrease of enantiomeric excess for the recovered mono adduct 4a was observed (74 % ee)( Table 4, Supporting Information, Experimental studies). Furthermore,r acemic mono adduct 4a was treated under identical conditions and was recovered with À10 % ee ( Table 4, Scheme 2).
These results indicate that the mono addition reaction in the presence of Ag/(R)-Fesulphos is ar eversible process in which the forward cycloaddition is enantioselective whereas the retrocycloaddition undergoes kinetic resolution. Similarly investigations with enone 1a and imine 2g further confirmed ad ynamic covalent mono cycloaddition (Supporting Information, Experimental studies).
Fore xamination of the second cycloaddition in the sequence from 4a to 3a enantioenriched mono addition product 4a (70 % ee)w as treated with 1equiv of iminoester 2a under racemic conditions.Nochange in enantioselectivity was observed for the double cycloaddition product 3a (70 % ee Table 5, Supporting Information, Experimental studies), thereby confirming that the stereochemistry is already set in the first step of the reaction sequence.H owever,e mploying enantioenriched 4a (70 % ee)i nt he presence of ac hiral catalyst led to adecrease in enantioselectivity for the double cycloaddition product 3a (60 % ee,T able 5; Supporting Information, Experimental studies).
Furthermore,w hen racemic mono addition product rac-4a was subjected to the cycloaddition in the presence of (R)-FeSulphos and AgOAc with 1equiv of iminoester 2a,double cycloaddition product 3a was obtained as an opposite

Angewandte Chemie
Research Articles enantiomer (À)3a with 20 % ee (Table 5, Scheme 2) and was confirmed by crystal structure analysis (Supporting Information, Experimental studies,C rystal Data). Thed ecreased enantioselectivity observed for 3a employing achiral catalyst may be due the enantioselective retrocycloaddition of 4a as discussed above (Table 5).
To further elucidate the reaction pathway,w ep erformed ak inetic experiment by reacting rac-4 a with imine 2a employing chiral catalyst (Supporting Information, Experimental studies,Supplementary Table 3). In the early stages of the reaction, 4a is rapidly converted into the endo, endoproduct (À)3a and an endo, exo-diastereomer (+ +)6 a (Scheme 3a,S upporting Information, Experimental studies,S upplementary Table 3). X-Ray analysis of the stereoisomeric endo,exo-product (+ +)6 a revealed that it is formed through an exo-selective cycloaddition of iminoester 2a to the endo monoaddition product (+ +)4 a (Supporting Information, Crystal Data). After three minutes,(À)3a and (+ +)6a are formed with noticeable ee (40 %and 37 % ee,respectively) (Supporting Information, Experimental studies,S upplementary Table 3). Over the course of the reaction, the ee of both products ((À)3a and (+ +)6a)d ecreases to 13 %a nd À13 % ee, respectively.Furthermore,the product ratio changes throughout the course of the reaction with more endo, endo-product 3a being formed over time while the yield of the endo, exoproduct 6a decreases over time (Supporting Information, Experimental studies,S upplementary Table 3). As imilar trend was observed by performing the kinetic experiment by subjecting racemic mono adduct rac-4 a to cycloaddition with iminoester 2g under chiral conditions (Supporting Information, Experimental studies,S upplementary Table 4).
Since rac-4 a is converted into two stereoisomers (À)3a and (+ +)6awith varying ratios and eesover time,itimplies the formation of kinetically and thermodynamically controlled products during an enantioselective dynamic covalent process resulting in interconversion of those stereoisomers.( Scheme 3a,S upporting Information Figure 1). The endo, exostereoisomer (+ +)6a is the kinetically favored product and is formed faster than the thermodynamically more stable product (À)3a.
These findings suggest that the double cycloaddition of enone 1 with imine 2 is in general adynamic covalent process which can be divided in two cycles (Supporting Information, Figure 2). First, aA g-/(R)-Fesulphos-catalyzed mono addition occurs to generate the chiral mono addition product 4 in which the chirality is set. Theinitial enantiopurity of the mono addition is > 95 % ee.
Over time,aselective retro-cycloaddition for the major enantiomer of mono adduct 4 is catalyzed by Ag-/(R)-Fesulphos which induces its decomposition and results in adecreased ee of monoaddition product 4 from > 95 % ee to 70-80 % ee (Table 3, Supporting Information, Figure 2). The main enantiomer of mono adduct 4 matches with the chiral environment of the Ag-/(R)-Fesulphos complex as its decomposition is faster compared to its enantiomer,r esulting in decrease of ee for mono adduct. In as econd cycle starting from the enantioenriched mono addition product 4,asecond cycloaddition takes place to generate ad ouble cycloaddition product. Here,two diastereomers are formed, the kinetically favored non-stable endo,e xo product 6 and the thermodynamically controlled stable endo, endo product 3 (Scheme 3a). Through ad ynamic covalent process,e nantioselective retro-cycloaddition of non-stable kinetic product endo, exo-6 a occurs generating mono addition product 4,w hich is then converted to the thermodynamically favored and stable endo, endo product 3 (Scheme 3b,S upporting Information, Figure 2).
In contrast, in DCM the endo, endo-product 3a is selectively obtained. Thei nversion in diastereoselectivity may be due to amore favorable exo-selective transition state in the aqueous environment. Alternatively interconversion of 6ato 3ais much slower in the aqueous solvent system relative to DCM. Thei nterconversion of the less stable kinetically favored endo, exo product 6 to the thermodynamically controlled product 3 might be as low equilibrium process which results in the kinetically controlled endo, exo product as major diastereomer in THF:H 2 O(Scheme 4). Thus the speed of isomerization of the stereoisomers is decreased. In DCM the interconversion to reach the thermodynamically controlled equilibrium may proceed faster, since the retro cycloaddition from kinetically favored endo,e xo product 6 to mono adduct 4 is more accelerated (Scheme 4). This was confirmed by analysis of the interconversion of the non-stable kinetic product endo, exo-6 a to its thermodynamically more stable endo, endo product 3a in both solvent systems. Subjecting Compound (+ +)6 a (95 % ee)t oA gOAc (6 mol %), (R)-Fesulphos (6.5 mol %) and Cs 2 CO 3 (40 mol %) in DCM afforded (+ +)3 a with 37 %y ield after 1h,w hile only traces were observed in aqueous conditions after 1h ( Table 7). Expansion of the substrate scope confirmed the diastereoselectivity trend favoring 6 over its thermodynamically more stable stereoisomer 3 when an aqueous solvent system (THF:H 2 O) was employed (Table 6).

Conclusion
In summary,w eh ave discovered an enantioselectively catalyzed dynamic covalent one-pot-tandem cycloaddition of azomethine ylides to a'-alkylidene-2-cyclopentenones.H igh diastereo-and enantioselectivity was obtained for the formation of the double cycloaddition products in at hermodynamically controlled equilibrium process.Astereodivergent synthesis was achieved since aswitch in diastereoselectivity is observed in aqueous solvent system (THF:H 2 O) and an enantiodivergent selectivity is recorded for reactions starting from racemic intermediate.O wing to differences in the reactivity of the endo-a nd exocyclic double bonds of the a'- alkylidene-2-cyclopentenones,two different dipoles could be successfully used in ao ne-pot process,y ielding structurally complex molecular frameworks with up to 8s tereocenters.