Stereospecific Hydroformylation of 1-Substituted Cyclopent-3-en-1-ols: A Concise Access to Bridged [2,2,1] Bicyclic Lactones With A Quaternary Stereocenter

: An efficient method lactones bearing a quaternary stereocenter was achieved by Rh-catalyzed asymmetric hydroformylation /intramolecular cyclization/PCC oxidation. By employing a hybrid phosphine-phosphite chiral ligand, a series of cyclopent-3-en-1-ols were transformed into their corresponding  -hydroxyl aldehydes with specific syn -selectivity, then hemiacetal formed in situ and oxidized by PCC in one-pot, affording 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. Gram-scale reaction and several transformations to corresponding amide, alcohol and acid demonstrated the practical value of this methodology.

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 asymmetric hydroformylation has been widely investigated and some significant progress have been made. 35,36,37,38,39,40,41,42,43,44,45 However, asymmetric hydroformylation is very sensitive to the steric hindrance of substrate, which make it difficult to tolerate tri-or tetrasubstituted alkenes. As a result, the construction of chiral aldehydes with a quaternary stereocenter and a tertiary stereocenter by asymmetric hydroformylation 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.
However, this transformation faces several challenges (Figure 2, c). First, it is very difficult to generate chiral aldehydes with exclusive syn-selectivity through asymmetric hydroformylation 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. Second, the generation of the hemiacetals is unfavourable 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. Herein, we report one-pot synthesis of chiral bridged [2,2,1] bicyclic lactones from readily available cyclopent-

Results
Reaction development and optimizations. Initially, considering only syn oxo-products can be transfered to corresponding bridged [2,2,1] bicyclic lactones, asymmetric hydroformylation of 1a was investigated to obtain 2a stereospecifically. When (S,S)-Ph-BPE, the representative ligand in AHF, 48 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 (entry 2). (R,R)-Quinoxp, which performed well in asymmetric hydrogenation reactions, 49,50,51,52,53 afforded taget product in low yield with moderate enantioselectivity (entry 3). The reaction was totally inhibitted when (S,S)-Me-Duphos and (S)-Segphos were employed. In order to obtain higher enantio-and diastereoselectivity, a series of YanPhos with different axial chirality, which were developed by our group, were evaluated. 54,55,56,57 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 (entries 6-13). When (S,R)-DM-YanPhos was employed (entry 11), the target product was obtained with the best diastereo-and enenatioselectivity.
After the completion of AHF, partial of reaction solution was took out for 1 H NMR to detect the conversion of AHF and the ratio of (2a+2a')/2a'', the rest of solution was treated with PCC to give target product 3a.
[b] Determined by 1 H NMR spectroscopy. [c] Determined by HPLC analysis on a chiral stationary phase.
[d] Isolated yield. ND = not detected. Having established the optimized reaction condition for asymmetric hydroformylation of 1a, we attempt to synthesize bridged [2,2,1] bicyclic lactone 3a in one pot by sequential AHF / intramolecular cyclization /dehydrogenation oxidation (  Under the optimal conditions, we investigated the substrate scope. All of the bridged [2,2,1] bicyclic lactones were prepared in good yields with excellent enantioselectivities (Figure 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. 60 Interestingly, 1-phenylcyclohept-4-en-  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 Figure 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, all-carbon substituted chiral spiro-lactones could also be efficiently synthsized by this strategy, delivering target products with good yields and high enantioselectivities (5b, 5c). ring-open reaction occurred, furnishing chiral amide 6 with high yield and excellent ee ( Figure   6, b). The hydroformylation product 2a can be efficiently reducted by NaBH4, affording chiral dual alcohol 7 in high yield (Figure 6, c). Under a mild condition, the bioactive chiral acid 8 was readily prepared by oxidation of 2m with H2O2 and NaClO2 (Figure 6, d). 61 were determined by HPLC analysis using a chiral stationary phase. The enantiomeric excesses of 3q-3u, 2w and 7 were determined by SHIMADZU gas chromatography using chiral capillary columns.
And the racemate bridged [2,2,1] bicyclic lactones were prepared with PPh3 as the ligand according to the general procedure described below: In a glovebox filled with argon, to a 5 mL vial equipped with a magnetic bar was added PPh3 (0.004 mmol) and Rh(acac)(CO)2 (0.002 mmol in 1 mL toluene). After stirring for 10 minutes, 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 (10 bar) and carbon monoxide (10 bar) were charged in sequence. The reaction mixture was stirred at 110 °C (oil bath) for 24 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 pyridinium chlorochromate (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. wrote the manuscript with feedback and guidance from H. L. and X.Z. All authors discussed the experimental results and commented on the manuscript.