A concise access to bridged [2,2,1] bicyclic lactones with a quaternary stereocenter via stereospecific hydroformylation

Chiral bridged [2,2,1] bicyclic lactones are privileged structural units in pharmaceutics and bioactive nature products. However, the synthetic methods for these compounds are rare. Here we report an efficient method for enantioselective construction of bridged [2,2,1] bicyclic lactones bearing a quaternary stereocenter via Rh-catalyzed asymmetric hydroformylation/intramolecular cyclization/pyridium chlorochromate (PCC) oxidation. By employing a hybrid phosphine-phosphite chiral ligand, a series of cyclopent-3-en-1-ols are transformed into corresponding γ-hydroxyl aldehydes with specific syn-selectivity. Then, hemiacetals form in situ and oxidation with PCC in one-pot affords bridged [2,2,1] bicyclic lactones in high yields and excellent enantiomeric excess. Replacing the hydroxyl group by an ester group, cyclopentanecarbaldehydes with a chiral all-carbon quaternary stereocenter in the γ-position can be generated efficiently.

Asymmetric hydroformylation (AHF) represents an efficient approach for asymmetric formation of C-C bond in an atomic economic manner [17][18][19][20][21][22][23][24][25] , and the aldehyde products can be easily converted to versatile functional compounds, such as chiral alcohols, acids, amines and esters [26][27][28][29][30][31][32][33][34] , thus AHF has been widely investigated and some significant progresses have been made [35][36][37][38][39][40][41][42][43][44][45] . However, most of the work focused on the AHF of monosubstituted olefins and disubstituted alkenes, and only one chiral center was introduced into the product. As a result, the construction of chiral aldehydes containing a quaternary center and a tertiary center simultaneously by AHF is rarely exploited. To the best of our knowledge, there was only one report achieved this transformation by using desymmetric hydroformylation strategy, but the substrate scope was limited to cyclopropenes with high ring strain. Furthermore, only moderate to good enantioselectivities were obtained (≤83% ee) 46 . Consequently, highly efficient synthesis of multichiral aldehydes bearing a quaternary stereocenter is still a problematic issue in this field.
Recently, our group developed a Rh-catalyzed AHF of 1,1disubstituted allyl alcohols to generate γ-butyrolactones 47 . We envisioned that the similar transformation might occur if 1-substituted cyclopent-3-en-1-ols were used as starting material, providing efficient access to bridged [2,2,1] bicyclic lactones with a quaternary stereocenter. However, this transformation faces several challenges (Fig. 2c). First, it is very difficult to generate chiral aldehydes with exclusive syn-selectivity through AHF of 1-substituted cyclopent-3-en-1-ols, but it's an essential factor to form bridged [2,2,1] bicyclic lactones in high yield. Moreover, the isomerization of alkene is difficult to be inhibited in AHF of cyclic olefines [48][49][50][51][52][53] , which further increases the difficulty of producing syn γ-hydroxyaldehydes. Second, the generation of the hemiacetals is unfavorable in this transformation because the large steric hindrance of tertiary alcohols greatly decreased the nucleophilic ability of hydroxy group to aldehydes. In addition, the relatively small steric difference between the two prochiral faces makes it difficult to obtain high enantioselectivity. Thus, the development of a highly efficient method for asymmetric synthesis of bridged [2,2,1] bicyclic lactones containing a quaternary stereocenter is still a challenge.

Results and discussion
Initially, considering only syn oxo-products can be transfered to corresponding bridged [2,2,1] bicyclic lactones, AHF of 1a was investigated to obtain 2a stereospecifically. When (S,S)-Ph-BPE, the representative ligand in AHF 54 , was employed, 1a was transformed into oxo-product with high conversion and excellent ee, along with good diastereoselectivity ( Table 1, entry 1). (Rc,Sp)-Duanphos showed low activity in this transformaiton albeit with good stereocontrol (Table 1, entry 2). (R,R)-Quinoxp, which performed well in asymmetric hydrogenation reactions 55-59 , afforded target product in low yield with moderate enantioselectivity (Table 1, entry 3). The reaction was totally inhibitted when (S,S)-Me-Duphos and (S)-Segphos were employed (Table 1,   entries [4][5]. In order to obtain higher enantio-and diastereoselectivity, a series of YanPhos-type ligands with different axial chirality (Fig. 3), which were developed by our group, were evaluated [60][61][62][63] . The results showed that all YanPhos-type ligands had good catalytic activity for this transformation, but there were big differences in the control of enantioselectivity and diastereoselectivity. Generally, YanPhos containing (S,R) axial chirality had better perfomance than that of YanPhos with (S,S) axial chirality ( Table 1, entries 6-13). When (S,R)-DM-YanPhos was employed (Table 1, entry 11), the target product was obtained with the best diastereo-and enenatioselectivity.
Having established the optimized reaction condition for AHF of 1a, we attempt to synthesize bridged [2,2,1] bicyclic lactone 3a in one pot by sequential AHF/intramolecular cyclization/dehydrogenation oxidation ( Table 2). Based on our previous work 64 , PCC (pyridinium chlorochromate) was selected as oxidant and delivered target product 3a with moderate yield (entry 1). Increasing reaction temperature could not improve the yield (entry 2). Considering the bulky steric hindrance greatly decreased the nucleophilicity of tertiary alcohol 65 , several additives were screened to promote the cyclization of 2a. Acetic acid lead to a significant drop in yield, NaOAc resulted in the decrease  of yield to some extent. To our delight, K 2 CO 3 , Cs 2 CO 3 and NEt 3 can promote this reaction, affording target product in high yield without compromising the enantioselectivity (entries 5-7). However, a racemization occurred when NaOH was used, resulting in the decrease of ee and dr values (entry 8, 40% yield, 80% ee). Thus, one practical method for synthesis of bridged [2,2,1] bicyclic lactones was most effective with (S,R)-DM-YanPhos as the ligand in AHF and NEt 3 as additive in PCC oxidation.
Under the optimal conditions, we investigated the substrate scope. All the bridged [2,2,1] bicyclic lactones were prepared in good yields with excellent enantioselectivities (Fig. 4). Substrates bearing halides on the phenyl ring performed well in this transformation, giving target products with high yields and excellent ee's (3b-3f). The absolute configuration of 3d was confirmed by X-ray crystallographic analysis. Electron-donating and electronwithdrawing substituted groups on the phenyl ring were also tolerated, furnishing 3f, 3g, 3h, 3i, 3j with high yields and   excellent enantioselectivities, respectively. The yield of 3k was dropped sharply due to the ortho effect of methoxy group, but the high enantioselectivity was remained. In addition, functional groups, such as trifloromethyl, phenyl and borate (3l-3n) on the para-position of the benzene ring were compatible, and the corresponding products were afforded with moderate to good yields and high ee's. Replacing phenyl by a naphthyl group (3o), the reaction also proceeded smoothly, providing the desired compound with high yield and excellent ee. Notably, alkyl substituents, such as benzyl, n-hexyl, isopropyl, cyclopropyl, cyclopentyl and cyclohexyl were also well tolerated in this transformation, delivering bridged [2,2,1] bicyclic lactones with excellent ee's and high yields (3p-3u). Cyclopent-3-en-1-ol bearing a bulky sterically hindered damantyl group also proceeded effectively, affording target product with high yield (3v). Moreover, the oxo-product 2w was produced with high diastereoselectivity and excellent enantioselectivity 66 . Interestingly, 1phenylcyclohept-4-en-1-ol, a challenge substrate for AHF because of the substituent far away from reaction site, which made it difficult to control the stereoselectivity, also worked very well in this transformation, delivering 6-oxabicyclo[3.2.2]nonan-7-one 3x with high yield and good enantioselectivity.
Encouraged by the success of desymmetric strategy for construction of chiral bridged [2,2,1] bicyclic lactones with a O-subsitituted quaternary center, primary exploration on efficient synthesis of cyclopentanecarbaldehyde with an all-carbon quaternary stereocenter was conducted. As shown in Fig. 5, when symmetric cyclopentene with phenyl and ester substituents was employed, the desired chiral aldehyde 5a was generated in good yield with high diastereo-and enantioselectivity. Moreover, allcarbon substituted chiral spiro-lactones could also be efficiently synthesized by this strategy, delivering target products with good yields and high enantioselectivities (5b, 5c).
To further demonstrate the practical utility of this methodology, a gram-scale reaction of 1d was conducted in the presence of 0.2 mol% catalyst, then treated with NEt 3 and PCC, 3d was obtained with high yield and without any loss in enantioselectivity (Fig. 6a). Under the classical conditions of Sonogashira reaction and Heck reaction, alkyne and alkene groups were effectively incorporated into 3d, and the chiral bridged [2,2,1] bicyclic lactone skeleton was not affected (Fig. 6b). In order to obtain the ring-opening derivatives of bridged [2,2,1] bicyclic lactones, 3d was treated with methanol solution of ammonia, furnishing chiral amide 8 with high yield and excellent ee (Fig. 6b). The hydroformylation product 2a can be efficiently reducted by NaBH 4 , affording chiral dual alcohol 9 in high yield (Fig. 6c). Under a mild condition, the bioactive chiral acid 10 was readily prepared by oxidation of 2m with H 2 O 2 and NaClO 2 (Fig. 6d) 67 .
Based on the experimental results and the related mechanisum studies on Rh/Yanphos catalyzed AHF in literature 27,61 , we proposed the possible stereochemical model to explain the reason for high stereoselectivity in this transformation. According to the orientation of substrate closed to the catalyst, there are two possible coordination models (Fig. 7). In model A, there is a large repulsion between the benzene ring of the substrate and the naphthalene ring of ligand, hence this model is disfavored. By comparison, the repusion betweeen substrate and catalyst is much smaller in model B due to the small streric hindrance of hydroxy group, thus the asymmetric hydrofomylation reaction occurred smoothly, delivering chiral γ-hydroxyaldehyde with excellent synselectivity, which can be efficiently transfer to the target bridged [2,2,1] bicyclic lactone in the presence of PCC.
In this work, we have developed an efficient and concise method for preparing bridged [2,2,1] bicyclic lactones bearing a quaternary stereocenter from readily available starting material by one-pot process. This methodology shows excellent substrate compatibility and excellent stereocontrol, giving target products with high yields and excellent enantioselectivities. In addtion, this protocol also provides a useful strategy for construction of chiral aldehydes with an all-carbon quaternary stereocenter. Gram-scale reaction and diverse transformations of the oxo-products and bridged [2,2,1] bicyclic lactones demonstrate the utility of this method in synthetic chemistry. Further exploration on the construction of quaternary chiral center by AHF is ongoing in our laboratory.

Methods
In a glovebox filled with argon, to a 5 mL vial equipped with a magnetic bar was added (S,R)-DM-YanPhos (0.004 mmol) and Rh(acac)(CO) 2 (0.002 mmol in 1 mL toluene). After stirring for 10 min, the mixture was charged to substrate (0.2 mmol). The vial was transferred into an autoclave and taken out of the glovebox. The argon gas was replacement with hydrogen gas for three times, and then hydrogen (2.5 bar) and carbon monoxide (2.5 bar) were charged in sequence. The reaction mixture was stirred at 70°C (oil bath) for 48 h. The reaction was cooled to room temperature and the pressure was carefully released in a well-ventilated hood. The solution was transferred into a solution of PCC (0.5 mmol) and triethylamine (0.1 mmol) in 4 mL dichloromethane, the reaction mixture was stirred at 25°C (oil bath) overnight. The solution was concentrated and the product was isolated by column chromatography using petrol ether/EtOAc (30:1-10:1) as eluent to give the desired product.

Data availability
The data supporting the findings of this study are available in the paper and its Supplementary Information, further data are available from the corresponding author on request. The X-ray crystallographic coordinates for structures reported in this study have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition numbers CCDC 2034549 (3d). These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.