Chiral Cyclohexyl-Fused Spirobiindanes - ACS Publications

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Article Cite This: J. Am. Chem. Soc. 2018, 140, 10374−10381

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Chiral Cyclohexyl-Fused Spirobiindanes: Practical Synthesis, Ligand Development, and Asymmetric Catalysis Zhiyao Zheng,†,# Yuxi Cao,†,‡,# Qinglei Chong,†,∥ Zhaobin Han,† Jiaming Ding,† Chenguang Luo,† Zheng Wang,† Dongsheng Zhu,‡ Qi-Lin Zhou,§,∥ and Kuiling Ding*,†,∥,⊥

J. Am. Chem. Soc. 2018.140:10374-10381. Downloaded from pubs.acs.org by UNIV OF SOUTH DAKOTA on 08/16/18. For personal use only.

†

State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China ‡ Department of Chemistry, Northeast Normal University, Changchun 130024, China § State Key Laboratory and Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China ∥ Collaborative Innovation Center of Chemical Science and Engineering, Nankai University, Tianjin 300071, China ⊥ University of Chinese Academy of Sciences, Beijing 100049, China S Supporting Information *

ABSTRACT: 1,1′-Spirobiindane has been one type of privileged skeleton for chiral ligand design, and 1,1′-spirobiindane-based chiral ligands have demonstrated outstanding performance in various asymmetric catalysis. However, the access to enantiopure spirobiindane is quite tedious, which obstructs its practical application. In the present article, a facile enantioselective synthesis of cyclohexyl-fused chiral spirobiindanes has been accomplished, in high yields and excellent stereoselectivities (up to >99% ee), via a sequence of Ir-catalyzed asymmetric hydrogenation of α,α′-bis(arylidene)ketones and TiCl4 promoted asymmetric spiroannulation of the hydrogenated chiral ketones. The protocol can be performed in one pot and is readily scalable, and has been utilized in a 25 g scale asymmetric synthesis of cyclohexyl-fused spirobiindanediol (1S,2S,2′S)-5, in >99% ee and 67% overall yield for four steps without chromatographic purification. Facile derivations of (1S,2S,2′S)-5 provided straightforward access to chiral monodentate phosphoramidites 6a−c and a tridentate phosphorus-amidopyridine 11, which were evaluated as chiral ligands in several benchmark enantioselective reactions (hydrogenation, hydroacylation, and [2 + 2] reaction) catalyzed by transition metal (Rh, Au, or Ir). Preliminary results from comparative studies showcased the excellent catalytic performances of these ligands, with a competency essentially equal to the corresponding well-established privileged ligands bearing a regular spirobiindane backbone. X-ray crystallography revealed a close resemblance between the structures of the precatalysts 20 and 21 and their analogues, which ultimately help to rationalize the almost identical stereochemical outcomes of reactions catalyzed by metal complexes of spirobiindane-derived ligands with or without a fused cyclohexyl ring on the backbone. This work is expected to stimulate further applications of this type of readily accessible skeletons in development of chiral ligands and functional molecules.

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INTRODUCTION

by optical resolution using substoichiometric resolving agents in the past decades.3,7 The asymmetric catalytic construction of SPINOL and related spirobiindanes, though challenging in the broad context of chiral spirocycle synthesis,8 is highly attractive from the viewpoint of practical synthesis.9 In addition, such a chemical innovation can provide access to more diversified and creative catalyst design through ligand design and total synthesis.10 In this respect, a recent report by Tan and coworkers is especially noteworthy, which disclosed the only

The sterically constrained features of the spiro structures make them excellent frameworks in construction of chiral ligands,1 and remarkable achievements have been made in this area since the late 1990s.2 In this context, a class of chiral ligands and organocatalysts featuring a 1,1′-spirobiindane3 backbone (Chart 1) are extraordinarily successful, which demonstrated outstanding performance in a host of asymmetric catalytic reactions.1,4−6 Currently, most synthetic approaches to this type of privileged ligands/catalysts4 relied heavily on functional group manipulation of enantiopure 1,1′-spirobiindane-7,7′-diol (SPINOL) and analogues,2c,3−5 which was generally obtained © 2018 American Chemical Society

Received: July 6, 2018 Published: July 23, 2018 10374

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Table 1. Ir(I)/(S)-tBu-PHOX Catalyzed Asymmetric Hydrogenation of 1a−pa

Chart 1. Selected Chiral Spiro Skeletons and Ligands

example so far on the successful catalytic enantioselective synthesis of SPINOL and its analogues.11 In this elegant work, chiral phosphoric acids were used as catalysts for enantioselective spirocyclization of achiral acetone derivatives, providing a variety of SPINOLs in good yields with excellent ee values. Previously in our efforts toward the development of chiral spiro ligands,2f−h,12 we have reported the first asymmetric synthesis of chiral aromatic spiroketals, based on a one-pot Ir(I)-catalyzed hydrogenation and spiroketalization of α,α′bis(2-hydroxyarylidene)ketones.2h We envisioned that this strategy might also work for synthesis of chiral cyclohexylfused spirobiindanes, e.g., via asymmetric hydrogenation13 of α,α′-bis(arylidene)cyclohexanones and stereoselective spiroannulation of the resulting chiral ketones. In this case, the carbonyl group in the hydrogenation product would be flanked by two vicinal chiral carbon centers, which may induce good stereochemical control in the ensuing spirocyclization. It is interesting to note that in addition to axial spiro chirality, such a reaction sequence can effectively establish two more chiral centers in the cyclohexyl-fused spirobiindanes. Such spirocycles are also expected to be conformationally more constrained than their regular spirobiindane analogues, and hence might provide an excellent platform for chiral ligand development and structure−reactivity relationship assessment. Herein, we report a scalable asymmetric synthesis of cyclohexyl-fused chiral spirobiindanes, preparation of ligands with this new chiral scaffold, comparative studies in enantioselective catalysis, as well as structural characterization of some precatalysts.

entry

Ar

R

product

yield (%)b

ee (%)c

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

Ph 2-MeC6H4 3-MeC6H4 4-MeC6H4 3-MeOC6H4 4-MeOC6H4 2-Naphthyl 2-Br-5-MeOC6H3 3,4-(MeO)2C6H3 2,5-Me2C6H3 2-Me-5-MeOC6H3 2,5-(MeO)2C6H3 2,3,4-(MeO)3C6H2 2-Br-5-MeOC6H3 2-Br-5-MeOC6H3 2-Br-5-MeOC6H3

H H H H H H H H H H H H H Me t Bu Ph

(S,S)-2a (S,S)-2b (S,S)-2c (S,S)-2d (S,S)-2e (S,S)-2f (S,S)-2g (S,S)-2h (S,S)-2i (S,S)-2j (S,S)-2k (S,S)-2l (S,S)-2m (S,S)-2n (S,S)-2o (S,S)-2p

90 94 82 90 97 95 95 97 97 95 90 89 94 95 93 90

>99 >99 >99 >99 >99 >99 >99 >99 >99 >99 99 >99 >99 >99 >99 >99

a

Conditions: 1 (0.2 mmol), Ir(I)/(S)-tBu-PHOX (0.002 mmol), H2 (30 atm), CH2Cl2 (5 mL), rt, 6 h. In each case, the dr value of hydrogenation product 2 (trans-2/cis-2) was determined to be >20/1 by 1H NMR analysis. bYields of the isolated products. cDetermined by HPLC analysis on chiral columns.

nulation would involve electrophilic activation of the carbonyl group by protonation, followed by two successive intramolecular Friedel−Crafts (FC) reactions of the nucleophilic phenyl groups leading to stereogenic formation of the spiro carbon center, and concomitant loss of an equivalent of water.16,17 For the double intramolecular FC reactions of chiral ketones (S,S)-2a−p, both Brønsted and Lewis acids can in principle be utilized to control the stereochemical outcomes of the products. Therefore, a variety of acids, including Brønsted and Lewis type, were examined for their efficiency in promoting the asymmetric spiroannulation using (S,S)-2h (>99% ee). As shown in Table 2, a large excess of polyphosphoric acid (PPA) worked well in promoting the reaction to give 3h in 72% isolated yield, nevertheless the resultant product 3h was essentially racemic (entry 1), probably due to the proton-promoted ketoenol tautomerization and racemisation of (S,S)-2h.18 On the other hand, the use of H3[W12PO40] as the promoter did not afford any expected product 3h (entry 2), instead a slightly racemized (S,S)-2h (56%, enantiopurity lowered from >99% ee to 95% ee) and meso-2h (44%) were observed in the recovered materials. Moreover, most of the tested Lewis acidic salts are completely inactive for the reaction in CH2Cl2 at 40 °C (entries 3−9). Gratifyingly, the strongly oxophilic Lewis acid titanium chloride turns out to be a valuable exception, affording the spirocycle 3h in 51% yield with 99% ee (entry 10). Further variations in temperature (entries 11−13), solvent polarity, and substrate concentration resulted in a substantial improvement in the outcome of transformation (for details, see SI). The spiroannulation of (S,S)-2h (0.05 M) was best conducted in CH2Cl2 at 0−25 °C for 6 h with 2.0 equiv of

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RESULTS AND DISCUSSION Cyclohexyl-Fused Chiral Spirobiindanes: Efficient and Scalable Synthesis. The α,α′-bis(arylidene)cyclohexanone substrates 1a−p were readily prepared by condensation of cyclohexanone with the corresponding aromatic aldehydes (for details, see SI). Since chiral Ir(I)/ phosphine-oxazoline complexes have been demonstrated particularly effective in the asymmetric hydrogenation of less functionalized alkenes,14 including α,β-unsaturated ketones,15 we surveyed some chiral Ir(I) precatalysts for asymmetric hydrogenation of 1a, and Ir(I)/(S)-tBu-PHOX turns out to be the best under the optimized reaction conditions (SI). Thus, the asymmetric hydrogenations of 1a−p were performed under 30 atm of H2 in dichloromethane at rt with 1.0 mol % Ir(I)/ (S)-tBu-PHOX as the catalyst. In all cases, the chiral α,α′bis(benzyl)ketones (S,S)-2a−p were obtained in high yields (≥82%) with excellent diastereoselectivities (trans/cis > 20 by 1 H NMR) and extremely high enantiopurities (≥99% ee) (Table 1), thus laying a good basis for ensuing transformations. Subsequently, a variety of acidic catalysts and reaction parameters were screened for diastereoselective spiroannulation of the resulting enantiopure ketones, of (S,S)-2h as the model substrate. Mechanistically, the acid promoted spiroan10375

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Table 3. TiCl4-Promoted Spiroannulation of 2a−pa−c

Table 2. Survey of Conditions for Spiroannulation of (S,S)2ha

entry

acid (equiv)

solvent

T (°C)

yield (%)b

ee (%)c

1 2 3 4 5 6 7 8 9 10 11d 12e 13f 14f,g

PPA (30) H3[W12PO40] (2) Sc(OTf)3 (2) In(OTf)3 (2) Cu(OTf)2 (2) AlCl3 (2) SnCl4 (2) FeCl3 (2) Ti(OiPr)4 (2) TiCl4 (2) TiCl4 (2) TiCl4 (2) TiCl4 (2) TiCl4 (2)

none toluene CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2

80 110 40 40 40 40 40 40 40 40 25 0 0−25 0−25

72 0 0 0 0 0 0 0 0 51 55 62 84 93

0 − − − − − − − − 99 >99 >99 >99 >99

a

Conditions: (S,S)-2h (0.2 mmol), solvent (2 mL), 12 h. bThe yield of isolated 3h. cThe ee value of (1S,2S,2′S)-3h was determined by HPLC on chiral stationary phase. dThe reaction time was 2 h. eThe reaction time was 20 h. fThe reaction time was 6 h (0 °C for 1 h, 25 °C for 5 h). g[(S,S)-2h] = 0.05 M.

TiCl4 (entry 14), to afford excellent yield (93%) of spirocycle 3h as a single enantiomer (>99% ee). The absolute configuration of 3h was established as (1S,2S,2′S) by X-ray crystallographic analysis of its demethylated diol derivative (4, see SI), indicating that the stereochemistry of the spiroannulation was completely substrate-controlled by the chirality of the trans-hydrogenated intermediate (S,S)-2h. Having established the optimal conditions for the asymmetric spiroannulation, we proceeded to examine the adaptability of the protocol. As shown in Table 3, analogous reactions of chiral ketones (S,S)-2a−p proceeded smoothly in the presence of two equivalents of TiCl4, affording the corresponding chiral spirobiindanes (1S,2S,2′S)-3a−p in moderate to high yields (45−93%) with generally excellent enantiomeric excesses (up to >99% ee). The reaction of the prototype substrate 2a (R = R′ = H) gave its corresponding product (1S,2S,2′S)-3a in 83% yield with 96% ee. The presence of activating groups, e.g., electron-donating methoxy and/or methyl groups on the phenyl rings, were found beneficial for the FC-type ring closure processes of ketones (S,S)-2b−f and (S,S)-2h−m. The spiroannulations proceeded efficiently under the mild conditions, providing the enantioenriched spirobiindanes (1S,2S,2′S)-3b−f and (1S,2S,2′S)-3h−m in 45−93% yields. The stereochemistry of the spirocyclization was wellcontrolled in most cases (90 → 99% ee), albeit partial racemization occurred in the reactions of (S,S)-2f and (S,S)2m (both bearing para-methoxy groups) by an unknown pathway which led to somehow lowered ee values in the corresponding products (1S,2S,2′S)-3f and (1S,2S,2′S)-3m. The ortho-, meta-, or para-methyl groups on the phenyl rings of 2b−d exhibited less significant effect on the enantioselectivities of the reactions, giving the relevant products [(1S,2S,2′S)-3b−

a

Conditions: (S,S)-2 (0.2 mmol), TiCl4 (0.4 mmol), CH2Cl2 (4 mL), 0−25 °C, 6 h. bYields of the isolated products. cee values were determined by HPLC on a chiral stationary phase.

d] in excellent ee values. The substrate (S,S)-2g bearing 2naphthyl groups underwent a smooth spirocyclization to give benzo-annulated spirobiindane (1S,2S,2′S)-3g with 99% ee. Finally, ketone substrates (S,S)-2n−p with alkyl (Me and t-Bu) or phenyl groups on the cyclohexyl backbones were also transformed to (1S,2S,2′S)-3n−p with 97 → 99% ees. These results set the stage for facile access to an enantiopure cyclohexyl-fused SPINOL derivative (1S,2S,2′S)-5, a new building block for synthesis of various chiral ligands and catalysts. In fact, asymmetric hydrogenation and spiroannulation can be combined in one-pot without purification and isolation of the hydrogenated intermediate. As shown in Scheme 1, using this procedure (1S,2S,2′S)-3h was readily prepared in a scale of tens grams in 84% yield.19 The target cyclohexyl-fused SPINOL (1S,2S,2′S)-5 was readily synthesized in 80% overall yield from (1S,2S,2′S)-3h, via BBr3 mediated demethylation and Pd-catalyzed hydrogenolytic debromination. It is especially noteworthy that the whole synthetic sequence was accomplished on a large scale without resorting to any chromatographic workup, and purification of 5 10376

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trapped by the other phenyl group via a second FC reaction, thus affording (1S,2S,2′S)-3 with retention of stereochemistries at both 2,2′-positions. In order to shed some light on the origin of extremely high ee values of most annulation products 3 even in the case using hydrogenated intermediates 2 containing small amount of meso-diastereomer (one-pot procedure), the control experiments were carried out to compare the reactivity of rac-2h and its meso-diastereomer. As shown in Scheme 2b, the reaction of meso-2h was very sluggish under the otherwise identical conditions, while the reaction of rac-2h gave rac-3h in 90% yield. This dramatic reactivity difference between rac- and mesodiastereomers suggests that a proper orientation of phenyl groups is a prerequisite for the cyclization to occur, which provides a rational basis for the viability of one-pot tandem hydrogenation-spiroannulation procedure in the presence of meso-2h byproduct mentioned above. The conformational analysis of meso-2h clearly showed that both benzyl groups should occupy equatorial α,α′-positions of cyclohexone (Scheme 2b), which renders the delivery of the phenyl group to one face (upper or lower) of the activated CO moiety virtually impossible. In contrast, the axial orientation of one benzyl group in rac-2h fulfills the spatial requirement for the interaction of phenyl ring with the activated CO group, hence allowing for the intramolecular FC reaction to occur. Synthesis of Chiral Ligands from (1S,2S,2′S)-5. Having established an efficient and scalable route to access enantiopure cyclohexyl-fused SPINOL analogue (1S,2S,2′S)5, we ventured into using this compound as a building block for construction of some new chiral ligands. In this context, chiral monodentate phosphoramidite ligands, which have found numerous catalytic applications with transition metals,22 came up as an appealing goal by virtue of their straightforward synthesis and structural variability. Hence, treatment of the diol (1S,2S,2′S)-5 with an appropriate aminophosphorous dichloride (Cl2PNR2) in the presence of triethylamine, led to ready access to the corresponding chiral spiro phosphoramidite ligands (1S,2S,2′S)-6a, (1S,2S,2′S,R N ,R N )-6b, and (1S,2S,2′S,SN,SN)-6c, respectively, in good yields (Scheme 3, see SI for details). The structures of 6a and 6c were characterized by single crystal X-ray diffractional studies (Scheme 3, inset figures). Notably, a strongly twisted eightmembered phosphadioxa ring was formed in both structures, at a cost of conformational change in the shape of cyclohexyl ring,

Scheme 1. Practical Preparation of an Enantiopure Cyclohexyl-Fused SPINOL Derivative (1S,2S,2′S)-5

was readily effected by crystallization, thus further attesting the practicality and scalability of the protocol (for details, see SI). Although the exact mechanistic pathway of the TiCl4 mediated spiroannulation of (S,S)-2 to (1S,2S,2′S)-3 is not completely clear at the present stage, a plausible mechanism was proposed on the basis of the stereochemical relationship between the synthetic precursor (S,S)-2 and the annulation product (1S,2S,2′S)-3 (Scheme 2a). Initially, the carbonyl Scheme 2. Proposed Mechanism for TiCl4-Mediated Spiroannulation (a), and Comparison of Reactivity for meso- and rac-2h (b)

Scheme 3. Synthesis of Monophosphoramidites 6a−c

oxygen of (S,S)-2 is coordinated to Lewis acidic TiCl4 to generate an intermediate A20 that is activated toward nucleophilic attack. Owing to the steric constraints of the α,α′-chirality on the cyclohexanone moiety, the first intramolecular FC reaction of A occurs through delivery of the phenyl group to one face (upper or lower) of the cyclohexanone, leading to the formation of titanium alkoxide B. The alkoxide B might undergo a Ti(IV)-assisted deoxygenation21 to generate a tertiary carbon cation C, which is immediately 10377

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Journal of the American Chemical Society which isomerized from chair in 5 into twist-boat in 6 during O−P bond formation in phosphoramidite synthesis. A new tridentate phosphorus-aminopyridine ligand (11), with the cyclohexyl-fused spirobiindane backbone, was also prepared by following an analogous procedure for preparation of SpiroPAP, via further derivatization of the OH groups in the key intermediate (1S,2S,2′S)-5. As shown in Scheme 4,

Scheme 5. Comparative Studies

Scheme 4. Synthesis of Tridentate P^N^N Ligand 11

Pd/rac-BINAP catalyzed coupling of bistriflate (1S,2S,2′S)-7 with diphenylmethanimine furnished the monoaminated triflate (1S,2S,2′S)-8, which underwent a phosphinylation in the presence of catalytic Pd(OAc)2/dppb. The resulting compound (1S,2S,2′S)-9, bearing a sterically bulky P(O)R2type moiety (R = 3,5-tBu2C6H3), was reduced by PhSiH3 to give the aminophosphine (1S,2S,2′S)-10. Finally, reductive amination using 3-methylpicolinaldehyde and NaBH(OAc)3 afforded the target ligand (1S,2S,2′S)-11 in a satisfactory overall yield for five steps (61%) (for details, see SI). Enantioselective Catalysis: A Comparative Study. Since 6a−c and 11 can be viewed as structural analogues of privileged SIPHOS5a,23 and SpiroPAP24 ligands, it was tempting for us to seek a comparison of their catalytic performances. As an exhaustive study of the relevant reactions would be impractical, we have surveyed ligands 6a−c and 11 in a cursory way for some benchmark metal-catalyzed reactions, selected on the basis of the literature precedents, using SIPHOS or SpiroPAP as the references. The results of these comparative studies are presented in Scheme 5, which showcased the outstanding characteristics of prepared ligands for asymmetric catalysis. Rh-catalyzed asymmetric hydrogenation (AH) of various dehydroamino acid derivatives has been extensively investigated for the synthesis of optically enriched chiral chemicals.13 Especially, cationic Rh-catalyzed AH of aminocinnamic acid derivative 12, owing to its mechanistically welldefined nature, has often served as a standard for test of chiral phosphorus ligands. In 2004, spinol-derived chiral monodentate phosphoramidite, SIPHOS-Me, has been demonstrated to be a highly enantioselective ligand for Rh catalyzed asymmetric hydrogenation of a range of functionalized olefins, and hydrogenation of 12 under 20 atm H2 at rt afforded 13 in 96% ee.23b Given these facts, we begin by examining ligand 6a in this model reaction. Gratifyingly, equally excellent results (full conversion, 96% ee) were achieved using 6a under otherwise identical conditions (Scheme 5a). 10378

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Journal of the American Chemical Society Catalytic asymmetric cycloadditions play a key role in asymmetric synthesis, since such transformations result in simultaneous formation of two or more new bonds with stereochemical control.25 In a recent publication, González group has demonstrated the utility of (S,RN,RN)-SIPHOS-PE in the Au-catalyzed asymmetric [2 + 2] reaction of Nallenylsulfonamides with vinylarenes for the facile synthesis of alkylidenecyclobutanes.26 Under otherwise identical conditions as optimized in this work, we have found that with (1S,2S,2′S,RN,RN)-6b as ligand, equally satisfactory results could be achieved on the model reaction of N-allenylsulfonamide 14 with 4-methoxystyrene, generating excelent yield (93%) and enantioselectivity (93% ee) for the four-membered ring 15 (Scheme 5b). Subsequently, we undertook a further comparative ligand evaluation in Rh-catalyzed asymmetric hydroacylation, with homoallylic sulfide 16 and salicylaldehyde as the model substrates (Scheme 5c). The prototype study was reported by Dong and co-workers, who have discovered that Spinolderived phosphoramidte (R,RN,RN)-SIPHOS-PE was superior in effecting such transformations.27 As anticipated, our phosphoramidite (1S,2S,2′S,SN,SN)-6c was found equally potent in regio- and stereocontrol of this reaction, affording the hydroacylation product 17 in 91% yield with >20:1 branched/linear regioselectivity and 92% ee (Scheme 5c). Finally, we moved on to examine the catalytic efficiency of the iridium complex of tridentate spiro P^N^N ligand (1S,2S,2′S)-11 in the asymmetric hydrogenation of acetophenone (Scheme 5d). In a recent work, an extremely efficient chiral iridium catalyst bearing the tridentate ligand SpiroPAP has been developed for asymmetric hydrogenation of ketones.24 A record-breaking TON value up to 4 550 000 (in a reaction time of 15 days) has been achieved in the hydrogenation of acetophenone, attesting the extraordinarily high stability and activity of the catalyst. From this perspective, we were intrigued whether the use of ligand (1S,2S,2′S)-11, structurally analogous to SpiroPAP, may lead to catalytic performance comparable to the latter in this reaction. In fact, up to 1 000 000 of TON (in 24 h) has been obtained in the hydrogenation of acetophenone with Ir/(1S,2S,2′S)-11 without any loss of enantioselectivity (98% ee, Scheme 5d). The utility of Ir/(1R,2R,2′R)-11 has also been demonstrated in the catalytic asymmetric hydrogenation of key intermediate (3R,4S)-18 for synthesis of chiral drug Ezetimibe,28 affording (3R,4S,3′S)-19 in 95% yield and 99:1 diastereoselectivity under a catalyst loading of 0.01 mol % (Scheme 5e). Characterization of Precatalyst Structures. The results from the comparative reaction studies clearly indicated that, in enantioselective catalysis, chiral ligands with a cyclohexyl-fused spirobiindane backbone are essentially parallel to their regular Spinol-derived analogues in conveying asymmetry and efficiency. To probe the origin of such a close resemblance in reaction behavior, we conducted further comparative structural studies for some selected precatalysts. Accordingly, we have characterized the crystal structures of the precatalysts [Rh(cod){(1S,2S,2′S)-6a}2](BF4)·(CH2Cl2)2 (20)and [Rh(COD)Cl((1S,2S,2′S,SN,SN)-6c)] (21) (for details, see SI). Figure 1 showed the X-ray crystal structures of 20 and 21 along with their counterparts, [Rh(cod){(S)-SIPHOS-Me}2](OH)·CH2Cl2 (CSD refcode: MORSIV)5a and [Rh(COD)Cl((R,RN,RN)-SIPHOS-PE)] (CSD refcode: EDEMEH),29 respectively, retrieved from the CSD database. A close inspection of the structure of 20, as shown in Figure 1a,

Figure 1. (a) Crystal structure of [Rh(cod){(1S,2S,2′S)-6a}2](BF4)· (CH2Cl2)2 (20). (b) Structural overlay of [Rh(cod){(1S,2S,2′S)6a}2](BF4)·(CH2Cl2)2 (20) and [Rh(cod){(S)-SIPHOS-Me}2](OH)·CH2Cl2 (MORSIV), where blue = 20, gray = MORSIV. In (a) and (b), solvent molecules, anions, and H atoms are omitted for clarity. (c) Crystal structures of [Rh(COD)Cl((1S,2S,2′S,SN,SN)-6c)] (21, left) and [Rh(COD)Cl((R,RN,RN)-SIPHOS-PE)] (EDEMEH, right).

revealed that Rh−P bond lengths [2.2901(19) and 2.261(2) Å] and P2−Rh1−P1 bite angle [93.80(7)°] are within the expected values. Similar to that in (1S,2S,2′S)-6a, the eightmembered phosphadioxa ring in 20 is strongly twisted. While the coordination geometry about the P atoms are pseudotetrahedral, the N atoms of the two ligands are trigonal planar. Most interestingly, an overlay of structures 20 and MORSIV revealed striking similarities between the two precatalysts (Figure 1b). Whereas the presence of two monodentate Pligands might in principle render considerable structural flexibility for 20 and MORSIV, nonetheless both precatalysts assume almost the same geometries, especially in the vicinity of the active Rh site. As a result of conformational constraints by cyclohexyl ring in 20, the spirobiindane rings in the two structures adopt slightly different spatial orientations. The cyclohexyls in 20 are far removed from the Rh center, and hence unlikely to exert significant steric effects on the catalysis. The close structural resemblance suggested that a reaction catalyzed by 20 or MORSIV is much likely to follow the same stereochemical course, hence giving almost identical results in the reaction (Scheme 5a). Figure 1c shows the crystal 10379

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structures of 21 and its analogue EDEMEH, which help understanding the reaction outcomes of the asymmetric hydroacylation catalyzed by these complexes (Scheme 5c). Ignoring the −(CH2)3− linkage at the backbone C2 and C2′ centers, 21 and EDEMEH can approximately be viewed as the mirror image of each other, with considerable similarities in their structural details. As a result, it is no wonder that using these two catalysts, the same ee values were obtained in the asymmetric hydroacylation (Scheme 5c).

The authors declare no competing financial interest. Crystallographic data (CIF files) for (2E,6E)-1l (CCDC 1406103), (1S,2S,2′S)-3g (CCDC 1406101), (1S,2S,2′S)-4 (CCDC 1406102), [(1S,2S,2′S)-5]2·Et3N (CCDC 1556728), (1S,2S,2′S)-6a (CCDC 1556898), (1S,2S,2′S,S N,S N)-6c (CCDC 1556899), 20 (CCDC 1556900), 21 (CCDC 1556901), and {[(1S,2S,2S′,R N ,R N )-6b]AuCl} (CCDC 1853631) have been deposited at the Cambridge Crystallographic Data Center.

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CONCLUSION In conclusion, a practical enantioselective synthesis of cyclohexyl-fused chiral spirobiindane derivatives has been realized. Ir-catalyzed asymmetric hydrogenation of α,α′bis(arylidene)ketones, followed by TiCl4 promoted asymmetric spiroannulation of the hydrogenated chiral ketones, afforded a variety of cyclohexyl-fused chiral spirobiindanes in excellent stereoselectivities (up to >99% ee). The protocol can be accomplished in one pot and is readily scalable, hence paving the way to practical utility of the skeletons. Some new chiral ligands bearing the cyclohexyl-fused spirobiindane backbone were easily accessed via further synthetic manipulations, and were evaluated in several asymmetric catalytic reactions. Results from comparative studies revealed that the catalytic competency of these ligands can largely rival the corresponding Spinol-derived privileged ligands. Crystallographic studies provided strong evidence for the overall structural similarities between precatalysts bearing spirobiindane backbone with or without the fused cyclohexyl rings, which ultimately help to rationalize the largely identical stereochemical outcomes of reactions catalyzed by these complexes. This work is expected to trigger further applications of this type of readily accessible skeletons in development of chiral ligands and functional molecules.

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ACKNOWLEDGMENTS This work was supported by Ministry of Science and Technology of China (Grant No. 2016YFA0202900), NSFC (Grant Nos. 21790333, 21421091), CAS (XDB20000000) and the Science and Technology Commission of Shanghai Municipality.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.8b07125. Detailed synthetic, crystallographic, and characterization data (PDF) Crystallographic data for (2E,6E)-1l (CIF) Crystallographic data for (1S,2S,2′S)-3g (CIF) Crystallographic data for (1S,2S,2′S)-4 (CIF) Crystallographic data for [(1S,2S,2′S)-5]2·Et3N (CIF) Crystallographic data for (1S,2S,2′S)-6a (CIF) Crystallographic data for (1S,2S,2′S,SN,SN)-6c (CIF) Crystallographic data for 20 (CIF) Crystallographic data for 21 (CIF) Crystallographic data for {[(1S,2S,2S′,RN,RN)-6b]AuCl} (CIF)

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AUTHOR INFORMATION

Corresponding Author

*[email protected] ORCID

Qi-Lin Zhou: 0000-0002-4700-3765 Kuiling Ding: 0000-0003-4074-1981 Author Contributions #

Z.Z. and Y.C. contributed equally. 10380

DOI: 10.1021/jacs.8b07125 J. Am. Chem. Soc. 2018, 140, 10374−10381

Article

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