Direct access to spirocycles by Pd/WingPhos-catalyzed enantioselective cycloaddition of 1,3-enynes

Spirocycles play an important role in drug discovery and development. The direct, catalytic, and enantioselective synthesis of spirocycles from readily available starting materials and in an atom economic manner remains a highly sought-after task in organic synthesis. Herein, an enantioselective Pd-hydride-catalyzed cycloaddition method for the synthesis of spirocyclic compounds directly from two classes of commonly available starting materials, 1,3-enynes and cyclic carbon−hydrogen (C−H) bonds, is reported. The reactions employ a chiral Pd/WingPhos catalyst to both suppress the formation of bis-allenyl by-products and control the stereoselectivity. 1,3-Enynes are used as dielectrophilic four-carbon units in the cycloaddition reactions, which also enables an enyne substrate-directed enantioselectivity switch with good levels of stereocontrol. The present spirocycle synthesis tolerates a broad range of functional groups of 1,3-enyne substrates, including alcohols, esters, nitriles, halides, and olefins. A variety of diverse cyclic nucleophiles, including pharmaceutically important heterocycles and carbocycles, can be flexibly incorporated with spiro scaffolds.

S pirocyclic scaffolds are widely present in numerous natural products and biologically active compounds [1][2][3][4][5][6][7] . Moreover, the uniquely rigid structures of spirocyclic scaffolds can reduce the conformational entropy penalty upon binding to a protein target 8,9 . As a result, spiro scaffolds have been increasingly utilized in drug discovery and development programs 8,9 . The development of efficient asymmetric approaches for constructing spirocyclic compounds has attracted much attention [10][11][12][13][14][15][16][17][18] . Despite considerable progress in the asymmetric synthesis of spirocycles, the methods that are direct, catalytic, enantioselective, and atom economic 19 and that rely on the use of commonly available starting materials are in high need.
However, the potential of this technique in the direct asymmetric synthesis of spirocyclic compounds has remained elusive. Moreover, the reported studies focused on asymmetric mono-hydroalkylation. In contrast, transition-metal-hydride-catalyzed asymmetric annulative double hydroalkylation sequences of unactivated unsaturated hydrocarbons with enols/enolates are scarce. In addition, effective chiral catalyst systems that are applicable to the establishment of asymmetric addition of enols/enolates to unsaturated hydrocarbons are comparatively limited. As our continuous interest in asymmetric cycloadditions [40][41][42][43][44][45][46] , we explored the possibility of transition-metal hydride-based cycloaddition strategy for the direct catalytic asymmetric spirocycle synthesis.
Here, we report the successful development of Pd-hydride catalyzed cycloaddition of 1,3-enynes employing P-chiral WingPhos as the ligand that enables the direct, atom-economical, and enantioselective synthesis of spirocycles from two classes of commonly available starting materials (Fig. 1a) selectivity issue of cycloaddition products versus double intermolecular hydroalkylation products has been addressed. A chiral Pd/WingPhos catalyst is able to affect both 1,3-enynes 1 having a terminal double bond and 1,3-enynes 1′ having a terminal triple bond to engage in the asymmetric cycloaddition reactions with high levels of enantioselectivity switch. Mechanistic studies suggest that two cycloaddition reactions involve mechanistically and stereochemically distinct processes. For the cycloaddition reaction with 1,3-enynes 1, the previously unreported enantioselective intermolecular hydroalkylation step of 1,3-enynes 1 with cyclic enols/enolates forms allene intermediates with axial chirality which serves as a chiral relay during cyclization processes involving a very high efficiency of axial-to central chirality transfer, whereas for the cycloaddition with 1,3-enynes 1′, the marked stereocenter of the spirocyclic products is directly introduced in the enantioselective intermolecular hydroalkylation step of 1,3-enynes 1′ with enols/ enolates to form allene intermediates with central chirality, which has not been previously realized. Table 1 Chiral ligand effects on product-selectivity and enantioselectivity a .

Results
Optimization of reaction conditions. We began the research by examining the cycloaddition reaction of 1,3-enynes having a terminal double bond with pyrazolidine-3,5-diones, a class of important heterocyclic scaffolds, which are widely present in biologically active molecules and pharmaceutical compounds [47][48][49][50] , for the asymmetric synthesis of spiro-pyrazolidine-3,5-diones. Spiro-pyrazolidine-3,5-diones have been shown to possess valuable biological properties, as exemplified by their use as AT1 angiotensin II receptor antagonists (Fig. 1b). However, there are no reports of catalytic asymmetric synthesis of spiro-pyrazolidine-3,5-diones, thus limiting their potential applications in discovering chiral bioactive molecules. The model reaction of 1,3-enyne 1a with pyrazolidine-3,5-dione 2a was initially investigated at CH 3   provide high levels of enantiocontrol. To our knowledge, the catalytic asymmetric cycloaddition which involves the terminal metal-butadienyl intermediates has not been previously reported. Tang and co-workers recently introduced P-chiral BIBOP-type ligands for various asymmetric catalytic reactions [51][52][53][54] . To our knowledge, this class of chiral ligands have not been successfully applied in the catalytic asymmetric hydroalkylation process of unactivated unsaturated hydrocarbons with enols/enolates. We tested this type of chiral ligands in the reaction of 1,3-enyne 1a and pyrazolidine-3,5-dione 2a, and found that WingPhos afforded promising results, with the formation of the desired spirocyclic product 3aa as the major product with high enantiocontrol ( annulative double hydroalkylation product 4aa, the temperature was decreased. The non-annulative double hydroalkylation product 4aa was fully suppressed, unfortunately, the reaction conversion decreased (Table 1, entry 8). We found that bases had a crucial effect on the reaction conversion (Table 2). BnN(Me) 2 , which has rarely been used as the base in organic synthesis, provided the desired spirocyclic product 3aa in 71% yield with 90% ee ( Table 2, entry 5 versus entries 1-4).
Substrate scope. With optimized chiral catalyst system and reaction conditions, a range of 1,3-enynes 1 have been examined for the cycloaddition reaction with 2a (Fig. 2).
(Hetero)aryl-substituted 1,3-enynes afforded spirocyclized products 3aa-3ja in good yields with high enantioselectivities. A 1,3-disubstituted enyne 1k also led to the spirocyclized product 3ka in 65% yield with 93% ee. Notably, alkyl-substituted 1,3enynes were also suitable substrates for this transformation (3la-3ua). Several functional groups were well tolerated, including esters, nitriles, halides, and free alcohols. Furthermore, alkenyl-substituted 1,3-enynes also underwent the cycloaddition to afford the corresponding spirocyclized products (3va-3wa). It is worth noting that such substrates have rarely been used in the reactions by transition-metal hydride catalysis, as could potentially generate multiple regioisomers of the butadienyl palladium intermediates and could lead to side products. 1,4-Disubstituted enynes did not work due to steric bulkiness. The absolute configuration of 3ea was determined by X-ray crystal analysis (for the details, see Supplementary Table 4 in the Supplementary  Information).
Notably, Pd/WingPhos catalyst also permitted the asymmetric cycloaddition reaction of 1,3-enynes having a terminal triple bond (Fig. 3). More interestingly, a switch of enantioselectivity was observed as compared with 1,3-enyne substrates having a terminal double bond.
Synthetic applications. To demonstrate the practicability of our method, a gram-scale synthesis of the spirocyclic compound 3aa was conducted without loss of the yield and enantioselectivity (Fig. 5a). The olefin group provided a versatile handle for rapid diversification to afford highly functionalized spirocyclic compounds 6−10 with up to three contiguous stereocenters (Fig. 5b). The amide group could be reduced by DIBAL-H to deliver valuable spiro-pyrazolidine 5. The N-N bond of 3ma could be cleaved with SmI 2 to afford functionalized cyclopentene 11 without loss of the enantioselectivity 55 .
Mechanistic studies. In order to gain insight into the reaction mechanism and understand the origin of the high enantioselectivity we observed in the Pd/WingPhos-catalyzed enantioselective cycloaddition reaction of 1,3-enynes 1, a series of experiments have been conducted (Fig. 6). We prepared the allene intermediates rac-13, (R a )-13, and (S a )-13 from pre-functionalized allenylic partners, rac-12, (R a )-12 (93% ee), and (S a )-12 (94% ee), respectively (We could not isolate the corresponding allene intermediate during the Pd/WingPhos-catalyzed cycloaddition reaction of 1a and 2a), and subjected them to the conditions of the enantioselective catalytic reaction. The cyclization of rac-13 led to the spirocyclic product 3ma with 0% ee (Fig. 6a), whereas the cyclization of (R a )-13 afforded (R)-3ma in 62% yield with 94% ee (Fig. 6b) and the cyclization of (S a )-13 afforded (S)-3ma in 65% yield and 92% ee (Fig. 6c). Taken together, these results suggest that axial chirality of the allene intermediates in situ generated via the Pd/WingPhos-catalyzed enantioselective intermolecular hydroalkylation of 1,3-enynes 1 with cyclic enols/ enolates likely serves as a chiral relay during the cyclization process involving a very high efficiency of axial-to central chirality transfer. In addition, the axially chiral allenes in situ generated must be stable to racemization under the reaction  conditions; otherwise no chirality transfer could be obtained. We also found that the allene intermediates (R a )-13 in the absence of ligand provided (R)-3ma in much higher yield (85% yield) with the same enantioselectivity (94% ee) (Fig. 6b).
On the basis of the above mechanistic studies and previous reports 36 , a plausible catalytic cycle for the cycloaddition reaction of 1,3-enynes is proposed in Fig. 7. The cycloaddition reaction of 1,3-enyne 1m having a terminal double bond involves the terminal Pd-butadienyl intermediate (Fig. 7a). First, the PdH species likely coordinates to 1,3-enyne 1m to form the complex A which undergoes migratory alkyne insertion 36 to produce the terminal butadienyl−Pd B1 or B2. Due to severe steric repulsion in B2, B1 is favored to undergo the intermolecular nucleophilic attack to afford chiral 1,3-disubstituted allene intermediate C with axial chirality. Subsequently, the intramolecular carbopalladation 56 of the chiral allene intermediate D forms E through a very high efficiency of axial-to central chirality transfer. The protodepalladation of E produces the spirocyclic product (R)-3ma. For the cycloaddition reaction of 1,3-enyne 1m′ having a terminal triple bond which involves the internal Pd-butadienyl intermediate (Fig. 7b), the intermolecular hydroalkylation of 1,3enyne 1m′ serves as the enantiodetermining step in which monosubstituted allene intermediate C′ with central chirality is formed.
Finally, we were interested in seeing whether the Pd-butadienyl intermediates generated by PdH insertion of 1,3-enynes differ with the corresponding intermediates generated by oxidative addition of allenol derivatives in reactivity or selectivity. We made the following comparison experiments (Fig. 8). Interestingly, the achiral enyne 1f as the precursor provided the cycloaddition product 3fa in 69% yield with 96% ee (Fig. 8a) whereas the racemic 2,3-allenyl acetate 1f″ as the precursor afforded the product 3fa in 66% yield with only 76% ee (Fig. 8b) under the identical reaction conditions. On the other hand, the achiral enyne 1f′ as the precursor provided the cycloaddition product ent-3fa in 50% yield with 93% ee (Fig. 8c) whereas the racemic 2,3-allenyl acetate 1f‴ as the precursor afforded the product ent-3fa in 45% yield with only 58% ee (Fig. 8d) under the identical reaction conditions. These results show the advantage and unique of the use of nonpolarized 1,3-enynes in the PdH-catalyzed asymmetric cycloaddition reactions in terms of not only atom economy but also enantioselectivity.

Discussion
We have developed a PdH-based cycloaddition strategy for the enantioselective synthesis of a series of spirocyclic compounds directly from two classes of commonly available starting materials, 1,3-enynes and activated cyclic carbon-hydrogen (C-H) bonds. In the present atom economic cycloaddition, nonpolarized 1,3-enynes are utilized as dielectrophilic four-carbon units. By employing P-chiral WingPhos as the chiral ligand, the challenging product selectivity issue of cycloaddition products versus double intermolecular hydroalkylation products has been addressed. Notably, a chiral Pd/WingPhos catalyst affects the enantioswitchable enyne cycloaddition reactions with high levels of stereocontrol, thus providing a protocol for the enantioselectivity switch by exchanging the position of double bond and triple bond of 1,3-enyne substrates while maintaining the same absolute configuration of the chiral catalyst [57][58][59] . A variety of diverse cyclic nucleophiles including pharmaceutically important heterocycles and carbocycles can be flexibly and directly incorporated with spiro scaffolds. A broad range of functional groups of 1,3-enyne substrates, including alcohols, esters, nitriles, halides, and olefins, are tolerated. We believe this methodology may find considerable use and enable the discovery of chiral spirocyclic molecules with interesting biological activities.