Enantioselective Construction of Bicyclic Pyran and Hydrindane

Aug 21, 2018 - Highly enantioselective intramolecular RC reactions via desymmetrization of cyclohexadienones have been developed. By employing ...
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Enantioselective Construction of Bicyclic Pyran and Hydrindane Scaffolds via Intramolecular Rauhut-Currier Reactions Catalyzed by Thiourea-Phosphines Kaizhi Li, Zhichao Jin, Wai-Lun Chan, and Yixin Lu ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b02706 • Publication Date (Web): 21 Aug 2018 Downloaded from http://pubs.acs.org on August 21, 2018

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Enantioselective Construction of Bicyclic Pyran and Hydrindane Scaffolds via Intramolecular Rauhut− −Currier Reactions Catalyzed by Thiourea− −Phosphines Kaizhi Li,1 Zhichao Jin,1 Wai-Lun Chan,1 and Yixin Lu*1,2 1

Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543, Singapore. National University of Singapore (Suzhou) Research Institute, 377 Lin Quan Street, Suzhou Industrial Park, Suzhou, Jiangsu, PR China, 215123

2

ABSTRACT: Highly enantioselective intramolecular RC reactions via desymmetrization of cyclohexadienones have been

developed. By employing cyclohexadienones with a flexible ether or alkyl group linked internal enone moiety, optically enriched bicyclic pyran and hydrindane skeletons were constructed. Bifunctional phosphine catalysts bearing a thiourea moiety were found to effectively promote the reaction, and preliminary studies suggest that the hydrogen bonding interaction between thiourea and carbonyl group is crucial and facilitates the otherwise flexible backbones to undergo the desired cyclization. KEYWORDS: Rauhut−Currier reaction, desymmetrization, bifunctional phosphine, thiourea, bicyclic pyran, hydrindane

The Rauhut−Currier (RC) reaction is a classic carbon carbon bond forming reaction1 that has found wide applications in the synthesis of natural products and biologically important agents.2 The past decade has witnessed tremendous advancement of catalytic asymmetric RC reactions promoted by various nucleophilic catalysts.3 In this context, enantioselective intramolecular RC reactions4 represent an efficient synthetic approach to quickly access complex molecular architectures. Compared to many specifically designed and constructed dielectrophilic substrates for intramolecular RC reactions, cyclohexadienone derivatives5 are particularly attractive and hold great practical values as they can be readily derived by oxidative dearomatization of phenol and its derivatives. In recent years, various catalytic processes have been developed for enantioselective desymmetrizations of cyclohexadionones, including: Michael addition,6 Stetter reactions7, the RC reactions4i-m and cascade reactions.8

Figure 1. Selected natural products and biologically active molecules containing bicyclic pyran and hydrindane backbones.

In the past few years, our group devised a family of amino acid-based chiral phosphine catalysts, and applied them to a wide range of enantioselective catalytic transformations.9 As part of our continued interest in asymmetric phosphine catalysis, we set our goal to develop novel approaches to

quickly access important structural motifs that are widely present in natural products and biologically significant molecules. In this context, bicyclic pyran and hydrindane scaffolds drew our attention (Figure 1).10 We envisioned that intramolecular RC reaction of cyclohexadienone derivatives may be utilized to construct these structures. Despite widespread applications of desymmetrizations of cyclohexadienones in organic synthesis, intramolecular RC reactions of cyclohexadienones are rather limited. Sasai and co-workers developed enantioselective synthesis of αalkylidene-γ-butyrolactones/α-methylidene-γ-lactams via intramolecular RC reactions.4i-4k Zhang and co-workers also reported a similar intramolecular RC reaction by employing chiral sulfonamide phosphine catalyst.4l Very recently, Huang et al. described an enantioselective synthesis of hydro-2Hindoles via a phosphine-catalyzed intramolecular RC reaction.4m Notably, all the above examples made use of cyclohexadienones with a terminal alkene, which are wellpositioned for the subsequent ring closure for the formation of fused five-membered ring systems. In order to synthesize bicyclic pyrans, substrates containing an internal alkene moiety may be used. Apparently, adding in an extra carbon results in a more flexible backbone, thus making the desired cyclization synthetically challenging. In addition, internal alkenes pose extra difficulty for phosphine activation (Scheme 1). Herein, we document utilization of amino acid-derived thiourea−phosphine catalysts in the intramolecular RC reaction of cyclohexadienones with pendant enone moieties, for highly enantioselective synthesis of bicyclic pyran and hydrindane skeletons.

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Scheme 1. Our hypothesis: accessing hydrindane and bicyclic pyran via desymmetrization of cyclohexadienone derivatives To construct bicyclic pyran structures, we chose cyclohexadienone 1a as a prototypical substrate, which was readily accessed via an installation of the oxygen atom and subsequent trivial structural elaboration. The intramolecular RC reaction of 1a in the presence of a number of amino acidderived phosphines was examined, and the results are summarized in Table 1. The cyclization turned out to be difficult, even when stoichiometric amount of methyldiphenylphosphine was employed, the desired product was only obtained in low yield (entry 1). We next examined amino acid-derived phosphines with different hydrogen bond donating groups. In the presence of phosphine catalyst containing a sulfaonamide (P1), a carbamate (P2), or an amide group (P3), no reaction was observed (entries 2−4). Gratifyingly, L-Val-derived P4 containing a thiourea moiety was able to promote the cyclization, and the desired RC product 2a was obtained in low yield and with low enantioselectivity (entry 5). Employment of thioureacontaining D-Thr-L-Val-derived dipeptide phosphine P5 led to dramatic improvement; 80% yield and 97% ee were attainable (entry 6). A range of dipeptidic phosphines with a thiourea moiety were subsequently investigated. While dipeptide phosphine P5 with a D-L- configuration was shown to be an excellent catalyst, astonishingly, catalyst P6 with an L-Lconfiguration was completely ineffective (entry 7). Among the different dipeptide phosphines screened, i.e. D-Thr-L-Phgbased P7, D-Thr-L-Phe-derived P8, L-tert-Leu-D-Thr-based P9, and L-Ala-D-Val-derived P10, phosphine P8 was found to be the best catalyst (entries 8−11). Notably, catalyst P9 furnished only trace amount of the desired product, presumably due to the steric hindrance introduced by the neighbouring tert-butyl group. Lowering catalyst loading of P8 gave inferior results (entry 12). Further enhancement of the RC reaction was possible with the utilization of Brønsted acidic phenol4i-j as an additive. With the employment of one equivalent phenol, the catalyst loading was reduced to 10 mol% (entry 13), further reducing the catalyst loading to 5 mol% led to slightly decreased yield and enantioselectivity (entry 14). Under the optimized reaction conditions, the intramolecular RC product 2a was obtained in 96% yield and with 96% ee (entry 13). A chiral amine catalyst, β-ICD, capable of catalysing our previously reported RC reaction of allenoates,4m was found ineffective (entry 15). With the establishment of the optimal reaction conditions, we next examined the scope of this intramolecular RC reaction and prepared different bicyclic pyrans, and the results are summarized in Table 2. The reaction was applicable to cyclohexadienone−enones bearing different aromatic moieties, regardless of the steric and electronic properties of the substituents on the aromatic ring; high yields and excellent ee values were attainable for all the examples examined (entries 1−10). The presence of ortho-substituent on the aryl group resulted in lower reactivity; much longer reaction time was

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required (entry 11). In addition, heteroaryl-containing enone substrates, as well as an enone bearing a vinylic substituent were well tolerated (Table 2, entries 14−16). The RC reaction was also applicable to cyclohexadienones with different alkyl substituents, all the cyclization products were obtained in good yields and with excellent enantioselectivities (entries 17−20). Notably, substituents containing an ester group could also be used in the reaction (entries 21 and 22), and such functional group tolerance offers an opportunity for further structural manipulations of the RC products Table 1. Catalyst screeninga

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

cat. (mol%) MePPh2 (100) P1 (20) P2 (20) P3 (20) P4 (20) P5 (20) P6 (20) P7 (20) P8 (20) P9 (20) P10 (20) P8 (10) P8 (10) P8 (5) β-ICD (20)

yield (%)b 20 NR NR NR 30 80 NR 80 88 trace 80 87 96 91 NR

ee (%)c -----36d -97 -97 97 --90 96 96 90 --

a Reaction conditions: 1a (0.05 mmol), and cat. in CHCl3 (1.0 mL) at room temperature for 24 h. bYield of isolated 2a. cThe ee values of 2a was determined by HPLC analysis on a chiral-stationary-phase column. d Denotes products with opposite configurations. ePhOH (1.0 equiv.) was used as the additive. NR = No reaction. β-ICD = β-Isocupreidine, Ts = 4toluenesulfonyl, TBS = tert-butyldimethylsilyl.

Having successfully developed the intramolecular RC pathway to prepare bicyclic pyrans, we next examine whether such an approach could be be extended to construct other fused ring systems. We focused on the synthesis of hydrindanes, structural motifs frequently found in natural products and bioactive molecules. Cyclohexadienone 3a with an internal enone moiety, readily derived from tyrosol, was chosen as a substrate to initiate our studies. As illustrated in Table 3, most phosphines screened could effectively catalyze the reaction (entries 1−10). Dipeptide phosphine L-Ala-D-Valbased P10 gave the best overall results; with phenol as additive, the desired RC product was obtained in 90% yield and with 92% ee (entry 11). The reaction scope was found to

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ACS Catalysis be broad, applicable to cyclohexadienones 3 with different aryl groups in enone structures (entries 12−22). Moreover, alkene structure in the enone moiety was also well-tolerated (entries 23 and 24). In all the examples examined, consistently high chemical yields and ee values were attained, and only one single diastereomer was formed. Attempt to extend current method for the construction of hydronaphthalenes was unsuccessful (entry 25). The absolute configuration of the products was determined based on X-ray crystal structural analysis of 4m (see the Supporting Information for details).11 The RC products are rich in functionality, thus suggesting facile further structural manipulations. As an illustration, a Michael addition and a hydrogenation of 2a led to bicyclic pyrans bearing a fused cyclohexane, in high yields, and without erosion of enantioselectivity (Scheme 2). Table 2. Enantioselective synthesis of bicyclic pyrans: the substrate scopea

entry

1

b

yield (%)b

ee (%)c

P1

18 (4a)

69

2

Ph (3a)

P2

68 (4a)

78

3

Ph (3a)

P3

4

Ph (3a)

P4

83 (4a) 80 (4a)

95 33

5

Ph (3a)

P5

83 (4a)

89

6

Ph (3a)

P6

28 (4a)

–31

7

Ph (3a)

P7

80 (4a)

–68

8

Ph (3a)

P8

80 (4a)

–76

9

Ph (3a)

P9

35 (4a)

11

10

Ph (3a)

P10

90 (4a)

92

11

d

Ph (3a)

P10

91 (4a)

95

12

d

4-OMePh (3b)

P10

91 (4b)

88

12d

4-OMePh (3b)

P10

91 (4b)

88 90 96

13

d

4-MePh (3c)

P10

92 (4c)

14

d

4-CNPh (3d)

P10

88 (4d)

15

d

4-NO2Ph (3e)

P10

89 (4e)

94

4-BrPh (3f)

P10

93 (4f)

93

1

R, R (1) Me, Ph (1a)

yield (%) 96 (2a)

2

Me, 4-OMePh (1b)

90 (2b)

94

16d

3

Me, 4-MePh (1c)

95 (2c)

95

17d

4-ClPh (3g)

P10

91 (4g)

94

4

Me, 4-CNPh (1d)

86 (2d)

92

18d

2-ClPh (3h)

P10

84 (4h)

96

5

Me, 4-NO2Ph (1e)

88 (2ed)

93

19

d

3,4-OMe2Ph (3i)

P10

85 (4i)

89

6

Me, 4-PhPh (1f)

93 (2f)

94

20

d

2-Naphthyl (3j)

P10

93 (4j)

95

7

Me, 4-BrPh (1g)

96 (2g)

94

21d

2-Furanyl (3k)

P10

85 (4k)

88

8

Me, 4-ClPh (1h)

95 (2h)

95

d

3-Phenanthryl (3l)

P10

92 (4l)

95

Me, 4-FPh (1i)

88 (2i)

94

10

Me, 3-BrPh (1j)

97 (2j)

94

23 24d

(E)-4-BrPhCH=CH (3m) P10 (E)-4-iPrPhCH=CH (3n) P10

e

94 (4m ) 90 (4n)

94 91

11f

25d

NR

NR

9

e

ee (%) 96

c

cat.

1

R (3)/n Ph (3a)

entry

Me, 2-ClPh (1k)

88 (2k)

94

g

Me, 3,4-OMe2Ph (1l)

85 (2l)

92

13

Me, 2-Naphthyl (1m)

92 (2m)

94

14e

Me, 2-Furanyl (1n)

86 (2n)

82

12

15

Me, 3-Thienyl (1o)

92 (2o)

91

16

Me, (E)-4-BrPhCH=CH (1p)

96 (2p)

92

17

Et, Ph (1q)

95 (2q)

97

18

n-Pr, Ph (1r)

96 (2r)

96

19

n-Bu, Ph (1s)

95 (2s)

97

20

PhCH2CH2CH2, Ph (1t)

96 (2t)

97

21

CH3CO2CH2CH2, Ph (1u)

97 (2u)

97

22

MeO2CCH2CH2, Ph (1v)

96 (2v)

95

a

Reaction conditions: 1 (0.05 mmol), P8 (10 mol%), and PhOH (1.0 equiv.) in CHCl3 (1.0 mL) at room temperature for 24 h. bYield of isolated product. cThe ee values were determined by HPLC analysis on chiral stationary phase. dThe absolute configuration of 2e (4S, 8S) was determined by X-ray crystallographic analysis. eThe catalyst loading was 20 mol%. fThe reaction time was 60 h. gThe reaction time was 36 h.

Table 3. The intramolecular Rauhut-Currier reaction for the synthesis of hydrindane backbonesa

22

d

Ph (3a’)

P10

a Reaction conditions: 3 (0.05 mmol) and P10 (10 mol%) in CHCl3 (1.0 mL) at room temperature for 12 h; n = 1 for entries 1 to 24, n = 2 for entry 25 bYield of isolated 4. cThe ee values of 4 were determined by HPLC analysis on chiral stationary phase. d PhOH (1.0 equiv.) was used as the additive. eThe absolute configuration of 4m (3R, 7S) was determined by X-ray crystallographic analysis. NR = No reaction.

Scheme 2. Synthetic manipulation of the intramolecular RC product We next intend to gain further understanding of this reaction, in particular, the high efficiency of phosphine−thiourea catalysts in promoting this otherwise difficult intramolecular RC reaction. Our proposed transition state model is shown in Scheme 3. We believe the hydrogen bonding interaction between the thiourea and the carbonyl oxygen of the enone moiety is crucial, which somewhat “locks”

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the flexible intermediate in a favourable position to ensure subsequent cyclization. The superior hydrogen bonding ability of thiourea (P8) to carbonyl oxygen, over other functional groups, i.e. tosyl (P1), carbamate (P2), and amide (P3), is the key reason behind the reactivity difference of various bifunctional phosphine catalysts. Interestingly, with the addition of thiourea P11 as a co-catalyst, bifunctional phosphines P1, P2, and P3 were able to catalyze the intramolecular RC reaction, although the conversions were low.

Scheme 3. Thiorea moiety plays a key role in the reaction In conclusion, we have developed novel intramolecular RC reactions via highly enantioselective desymmetrization of cyclohexadienones bearing an internal enone moiety, for the facile construction of bicyclic pyrans and hydrindane scaffolds. Thiourea-containing bifunctional phosphine catalysts proved to be efficient in promoting the cyclization of cyclohexadienone substrates with a flexible pendant chain structure. The strategy disclosed in this report may be applied for building other useful bicyclic structures from readily available phenol precursors. We are currently working in this research direction, and will report our findings in due course.

ASSOCIATED CONTENT Supporting Information Experimental procedures and spectral data for all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION Corresponding Author * Email: [email protected]

Notes The authors declare no competing financial interests.

ACKNOWLEDGMENT Y. L. thanks the Singapore National Research Foundation, Prime Minister’s Office for the NRF Investigatorship Award (R-143000-A15-281). Financial support from the National University of Singapore (R-143-000-695-114) is also gratefully acknowledged.

REFERENCES (1) For selected reviews on the RC reaction, see: (a) Methot, J. L.;

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Roush, W. R. Nucleophilic Phosphine Organocatalysis. Adv. Synth. Catal. 2004, 346, 1035–1015. (b) Aroyan, C. E.; Dermenci, A.; Miller, S. J. The Rauhut–Currier Reaction: A History and Its Synthetic Application. Tetrahedron 2009, 65, 4069–4084. (c) Xie, P.; Huang, Y. Domino Cyclization Initiated by Cross–Rauhut–Currier Reactions. Eur. J. Org. Chem. 2013, 6213–6226. (d) Bharadwaj, K. C. Intramolecular Morita–Baylis–Hillman and Rauhut–Currier Reactions. A Catalytic and Atom Economic Route for Carbocycles and Heterocycles. RSC Adv. 2015, 5, 75923–75946. (2) For selected examples on the application of the RC reaction in total synthesis, see: (a) Ergüden, J.-K. H.; Moore, W. A New Tandem Route to Angular Tetraquinanes. Synthesis of the Waihoensene Ring System Org. Lett. 1999, 1, 375–378. (b) Mergott, D. J.; Frank, S. A.; Roush, W. R. Application of the Intramolecular Vinylogous Morita−Baylis−Hillman Reaction toward the Synthesis of the Spinosyn A Tricyclic Nucleus. Org. Lett. 2002, 4, 3157–3160. (c) Agapiou, K.; Krische, M. J. Catalytic Crossed Michael Cycloisomerization of Thioenoates:  Total Synthesis of (±)Ricciocarpin A. Org. Lett. 2003, 5, 1737–1740. (d) Methot, J. L.; Roush, W. R. Synthetic Studies toward FR182877. Remarkable Solvent Effect in the Vinylogous Morita−Baylis−Hillman Cyclization. Org. Lett. 2003, 5, 4223–4226. (e) Mergott, D. J.; Frank, S. A.; Roush, W. R. Total Synthesis of (–)-Spinosyn A. Proc. Natl. Acad. Sci. USA 2004, 101, 11955–11959. (f) Stark, L. M.; Pekari, K.; Sorensen, E. J. A Nucleophile-Catalyzed Cycloisomerization Permits a Concise Synthesis of (+)-Harziphilone. Proc. Natl. Acad. Sci. USA 2004, 101, 12064–12066. (g) Winbush, S. M.; Mergott, D. J.; Roush, W. R. Total Synthesis of (−)-Spinosyn A:  Examination of Structural Features That Govern the Stereoselectivity of the Key Transannular Diels−Alder Reaction. J. Org. Chem. 2008, 73, 1818–1829. (h) Dermenci, A.; Selig, P. S.; Domaoal, R. A.; Spasov, K. A. Anderson, K. S.; Miller, S. J. Quasi-Biomimetic Ring Contraction Promoted by a Cysteine-Based Nucleophile: Total Synthesis of Sch-642305, Some Analogs and Their Putative Anti-HIV Activities. Chem. Sci. 2011, 2, 1568–1572. (3) For selected examples of enantioselective intermolecular RC reactions, see: (a) Zhao, Q.-Y.; Pei, C.-K.; Guan, X.-Y.; Shi, M. Enantioselective Intermolecular Rauhut−Currier Reaction of Electron−Deficient Allenes with Maleimides. Adv. Synth. Catal. 2011, 353, 1973–1979. (b) Dong, X.; Liang, L.; Li, E.; Huang, Y. Highly Enantioselective Intermolecular Cross Rauhut–Currier Reaction Catalyzed by a Multifunctional Lewis Base Catalyst. Angew. Chem. Int. Ed. 2015, 54, 1641–1644. (c) Zhou, W.; Su. X.; Tao, M.; Zhu, C.; Zhao, Q.; Zhang, J. Chiral Sulfinamide Bisphosphine Catalysts: Design, Synthesis, and Application in Highly Enantioselective Intermolecular Cross−Rauhut−Currier Reactions. Angew. Chem. Int. Ed. 2015, 54, 14853–14857. (d) Zhou, W.; Chen, P.; Tao, M.; Su, X.; Zhao, Q.; Zhang, J. Enantioselective Intermolecular Cross Rauhut– Currier Reactions of Activated Alkenes with Acrolein. Chem. Commun. 2016, 52, 7612–7615. (e) Li, S.; Liu, Y.; Huang, B.; Zhou, T.; Tao, H.; Xiao, Y.; Liu, L.; Zhang, J. Phosphine-Catalyzed Asymmetric Intermolecular Cross-Vinylogous Rauhut–Currier Reactions of Vinyl Ketones with para-Quinone Methides. ACS Catal. 2017, 7, 2805–2809. For selected examples of RC reaction-initiated enantioselective domino cyclizations, see: (f) Shi, Z.; Yu, P.; Loh, T.P.; Zhong, G. Catalytic Asymmetric [4 + 2] Annulation Initiated by an Aza–Rauhut–Currier Reaction: Facile Entry to Highly Functionalized Tetrahydropyridines. Angew. Chem. Int. Ed. 2012, 51, 7825–7829. (g) Jin, Z.; Yang, R.; Du, Y.; Tiwari, B.; Ganguly, R.; Chi, Y. R. Enantioselective Intramolecular Formal [2 + 4] Annulation of Acrylates and α,β-Unsaturated Imines Catalyzed by Amino Acid Derived Phosphines. Org. Lett. 2012, 14, 3226–3229. (h) Wang, H.; Zhou, W.; Tao, M.; Hu, A.; Zhang, J. Functionalized Tetrahydropyridines by Enantioselective Phosphine-Catalyzed Aza-[4 + 2] Cycloaddition of N-Sulfonyl-1-aza-1,3-dienes with Vinyl Ketones. Org. Lett. 2017, 19, 1710–1713. (4) For selected examples on the enantioselective intramolecular RC reaction, see: (a) Aroyan, C. E.; Miller, S. J. Enantioselective Rauhut−Currier Reactions Promoted by Protected Cysteine. J. Am. Chem. Soc. 2007, 129, 256–257. (b) Aroyan, C. E.; Dermenci, A.; Miller, S. J. Development of a Cysteine-Catalyzed Enantioselective

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ACS Catalysis Rauhut−Currier Reaction. J. Org. Chem. 2010, 75, 5784–5796. (c) Osuna, S.; Dermenci, A.; Miller, S. J.; Houk, K. N. The Roles of Counterion and Water in a Stereoselective Cysteine−Catalyzed Rauhut−Currier Reaction: A Challenge for Computational Chemistry. Chem. Eur. J. 2013, 19, 14245–14253. (d) Marqués-López, E.; Herrera, R. P.; Marks, T.; Jacobs, W. C.; Könning, D.; de Figueiredo, R. M.; Christmann, M. Crossed Intramolecular Rauhut−Currier-Type Reactions via Dienamine Activation. Org. Lett. 2009, 11, 4116–4119. (e) Wang, X.-F.; Peng, L.; An, J.; Li, C.; Yang, Q.-Q.; Lu, L.-Q.; Gu, F.-L.; Xiao, W.-J. Enantioselective Intramolecular Crossed Rauhut−Currier Reactions through Cooperative Nucleophilic Activation and Hydrogen−Bonding Catalysis: Scope and Mechanistic Insight. Chem. Eur. J. 2011, 17, 6484–6491. (f) Gong, J.-J.; Li, T.-Z.; Pan, K.; Wu, X.-Y. Enantioselective Intramolecular Rauhut–Currier Reaction Catalyzed by Chiral Phosphinothiourea. Chem. Commun. 2011, 47, 1491–1493. (g) Zhang, X.-N.; Shi, M. A Highly Nucleophilic Multifunctional Chiral Phosphane-Catalyzed Asymmetric Intramolecular Rauhut–Currier Reaction. Eur. J. Org. Chem. 2012, 6271–6279. (h) Scanes, R. J. H.; Grossmann, O.; Grossmann, A.; Spring, D. R. Enantioselective Synthesis of Chromanones via a Peptidic Phosphane Catalyzed Rauhut–Currier Reaction. Org. Lett. 2015, 17, 2462–2465. (i) Takizawa, S.; Nguyen, T. M.-N.; Grossmann, A.; Enders, D.; Sasai, H. Enantioselective Synthesis of α-Alkylidene-γ-Butyrolactones: Intramolecular Rauhut– Currier Reaction Promoted by Acid/Base Organocatalysts. Angew. Chem. Int. Ed. 2012, 51, 5423–5426. (j) Takizawa, S.; Nguyen, T. M.-N.; Grossmann, A.; Suzuki, M.; Enders, D.; Sasai, H. Facile Synthesis of α-Methylidene-γ-Butyrolactones: Intramolecular Rauhut–Currier Reaction Promoted by Chiral Acid–Base Organocatalysts. Tetrahedron 2013, 69, 1202–1209. (k) Kishi, K.; Arteaga, F. A.; Takizawa, S.; Sasai, H. Multifunctional Catalysis: Stereoselective Construction of α-Methylidene-γ-Lactams via an Amidation/Rauhut–Currier Sequence. Chem. Commun. 2017, 53, 7724–7727. (l) Su, X.; Zhou, W.; Li, Y.; Zhang, J. Design, Synthesis, and Application of a Chiral Sulfinamide Phosphine Catalyst for the Enantioselective Intramolecular Rauhut–Currier Reaction. Angew. Chem. Int. Ed. 2015, 54, 6874–6877. (m) Jin, H.; Zhang, Q.; Li, E.; Jia, P.; Li, N.; Huang, Y. Phosphine-Catalyzed Intramolecular Rauhut–Currier Reaction: Enantioselective Synthesis of Hydro-2HIndole Derivatives. Org. Biomol. Chem. 2017, 15, 7097–7101. (n) Yao, W.; Dou, X.; Wen, S.; Wu, J.; Vittal, J. J.; Lu, Y. Enantioselective Desymmetrization of Cyclohexadienones via an Intramolecular Rauhut–Currier Reaction of Allenoates. Nat. Commun. 2016, 7, 13024–12031. (5) For selected reviews on catalytic enantioselective desymmetrizations of prochiral dienone systems, see: (a) Maertens, G.; Ménard, M.-A.; Canesi, S. Catalytic Enantioselective Desymmetrizations of Prochiral Dienone Systems. Synthesis 2014, 46, 1573–1582. (b) Kalstabakken, K. A.; Harned, A. M. Asymmetric Transformations of Achiral 2,5-Cyclohexadienones. Tetrahedron 2014, 70, 9571–9585. (6) For selected examples on the enantioselective Michael reactions of cyclohexadienones, see: (a) Hayashi, Y.; Gotoh, H.; Tamura, T.; Yamaguchi, H.; Masui, R.; Shoji, M. Cysteine-Derived Organocatalyst in a Highly Enantioselective Intramolecular Michael Reaction. J. Am. Chem. Soc. 2005, 127, 16028–16029. (b) Vo, N. T.; Pace, R. D. M.; O’Hara, F.; Gaunt, M. J. An Enantioselective Organocatalytic Oxidative Dearomatization Strategy. J. Am. Chem. Soc. 2008, 130, 404–405. (c) Leon, R.; Jawalekar, A.; Redert, T.; Gaunt, M. J. Catalytic Enantioselective Assembly of Complex Molecules Containing Embedded Quaternary Stereogenic Centres from Simple Anisidine Derivatives. Chem. Sci. 2011, 2, 1487–1490. (d) Corbett, M. T.; Johnson, J. S. Enantioselective Synthesis of Hindered Cyclic Dialkyl Ethers via Catalytic Oxa-Michael/Michael Desymmetrization. Chem. Sci. 2013, 4, 2828–2832. (e) Tello-Aburto, R., Kalstabakken, K. A., Volp, K. A.; Harned, A. M. Regioselective and Stereoselective Cyclizations of Cyclohexadienones Tethered to Active Methylene Groups. Org. Biomol. Chem. 2011, 9, 7849–7859. (f) Gu, Q.; You, S.-L. Desymmetrization of Cyclohexadienones via Asymmetric Michael Reaction Catalyzed by Cinchonine-Derived Urea. Org. Lett. 2011, 13, 5192–5195. For selected examples on the

enantioselective heteroatom conjugate addition reactions of cyclohexadienones, see: (g) Gu, Q.; Rong, Z.-Q.; Zheng, C.; You, S.L. Desymmetrization of Cyclohexadienones via Brønsted AcidCatalyzed Enantioselective Oxo-Michael Reaction. J. Am. Chem. Soc. 2010, 132, 4056–4057. (h) Gu, Q.; You, S.-L. Desymmetrization of Cyclohexadienones via Cinchonine Derived Thiourea-Catalyzed Enantioselective Aza-Michael Reaction and Total Synthesis of (-)Mesembrine. Chem. Sci. 2011, 2, 1519–1522. (i) Ratnikov, M. O.; Farkas, L. E.; Doyle, M. P. Tandem Sequence of Phenol Oxidation and Intramolecular Addition as a Method in Building Heterocycles. J. Org. Chem. 2012, 77, 10294–10303. (j) Wu, W.; Li, X.; Huang, H.; Yuan, X.; Lu, J.; Zhu, K.; Ye, J. Asymmetric Intramolecular OxaMichael Reactions of Cyclohexadienones Catalyzed by a Primary Amine Salt. Angew. Chem. Int. Ed. 2013, 52, 1743–1747. (k) Li, J.; Liu, G.-L.; Zhao, X.-H.; Du, J.-Y.; Qu, H.; Chu, W.-D.; Ding, M.; Jin, C.-Y.; Wei, M.-X.; Fan, C.-A. Formal Synthesis of (±)-Morphine. Chem. Asian J. 2013, 8, 1105–1109. (7) For selected examples on the enantioselective Stetter reactions of cyclohexadienones, see: (a) Liu, Q.; Rovis, T. Asymmetric Synthesis of Hydrobenzofuranones via Desymmetrization of Cyclohexadienones Using the Intramolecular Stetter Reaction. J. Am. Chem. Soc. 2006, 128, 2552–2553. (b) Liu, Q.; Rovis, T. Enantioselective Synthesis of Hydrobenzofuranones Using an Asymmetric Desymmetrizing Intramolecular Stetter Reaction of Cyclohexadienones. Org. Process Res. Dev. 2007, 11, 598–604. (c) Jia, M.-Q.; You, S.-L. Desymmetrization of Cyclohexadienones via D-Camphor-Derived Triazolium Salt Catalyzed Intramolecular Stetter Reaction. Chem. Commun. 2012, 6363–6365. (d) Jia, M.-Q.; Liu, C.; You, S.-L. Diastereoselective and Enantioselective Desymmetrization of α-Substituted Cyclohexadienones via Intramolecular Stetter Reaction. J. Org. Chem. 2012, 77, 10996–11001. (e) Jia, M.-Q.; You, S.-L. Desymmetrization of Cyclohexadienones via Intramolecular Stetter Reaction to Construct Tricyclic Carbocycles. Synlett 2013, 1201–1204. (8) For selected examples on the enantioselective cascade reactions of cyclohexadienones, see: (a) Rubush, D. M.; Morges, M. A.; Rose, B. J.; Thamm, D. H.; Rovis, T. An Asymmetric Synthesis of 1,2,4Trioxane Anticancer Agents via Desymmetrization of Peroxyquinols through a Brønsted Acid Catalysis Cascade. J. Am. Chem. Soc. 2012, 134, 13554–13557. (b) Takizawa, S.; Kishi, K.; Yoshida, Y.; Mader, S.; Arteaga, F. A.; Lee, S.; Hoshino, M.; Rueping, M.; Fujita, M.; Sasai, H. Phosphine-Catalyzed β,γ-Umpolung Domino Reaction of Allenic Esters: Facile Synthesis of Tetrahydrobenzofuranones Bearing a Chiral Tetrasubstituted Stereogenic Carbon Center. Angew. Chem. Int. Ed. 2015, 54, 15511–15515. (c) Du, J.-Y.; Zeng, C.; Han, X.-J.; Qu, H.; Zhao, X.-H.; An, X.-T.; Fan, C.-A. Asymmetric Total Synthesis of Apocynaceae Hydrocarbazole Alkaloids (+)Deethylibophyllidine and (+)-Limaspermidine. J. Am. Chem. Soc. 2015, 137, 4267–4273. (d) Kishi, K.; Takizawa, S.; Sasai, H. Phosphine-Catalyzed Dual Umpolung Domino Michael Reaction: Facile Synthesis of Hydroindole- and Hydrobenzofuran-2Carboxylates. ACS Catal. 2018, 8, 5228–5232. (9) For selected reviews on phosphine catalysis, see: (a) Lu, X.; Zhang, C.; Xu, Z. Reactions of Electron-Deficient Alkynes and Allenes under Phosphine Catalysis. Acc. Chem. Res. 2001, 34, 535– 544. (b) Ye, L.-W.; Zhou, J.; Tang, Y. Phosphine-Triggered Synthesis of Functionalized Cyclic Compounds. Chem. Soc. Rev. 2008, 37, 1140–1152. (c) Cowen, B. J.; Miller, S. J. Enantioselective Catalysis and Complexity Generation from Allenoates. Chem. Soc. Rev. 2009, 38, 3102–3116. (d) Wang, S.-X.; Han, X.; Zhong, F.; Wang, Y.; Lu, Y. Novel Amino Acid Based Bifunctional Chiral Phosphines. Synlett 2011, 2766–2778. (e) Fan, Y. C.; Kwon, O. Advances in Nucleophilic Phosphine Catalysis of Alkenes, Allenes, Alkynes, and MBHADs. Chem. Commun. 2013, 49, 11588–11619. (f) Wei, Y.; Shi, M. Applications of Chiral Phosphine-Based Organocatalysts in Catalytic Asymmetric Reactions. Chem. Asian J. 2014, 9, 2720–2734. (g) Li, W.; Zhang, J. Recent Developments in the Synthesis and Utilization of Chiral β-Aminophosphine Derivatives as Catalysts or Ligands. Chem. Soc. Rev. 2016, 45, 1657–1677. (h) Wang, T.; Han, X.; Zhong, F.; Yao, W.; Lu, Y. Amino Acid-Derived Bifunctional Phosphines for Enantioselective Transformations. Acc. Chem. Res. 2016, 49, 1369–

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1378. (i) Li, H.; Lu, Y. Enantioselective Construction of All-Carbon Quaternary Stereogenic Centers by Using Phosphine Catalysis. Asian J. Org. Chem. 2017, 6, 1130–1145. For our selected recent examples, see: (j) Ni, H.; Tang, X.; Zheng, W.; Yao, W.; Ullah, N.; Lu, Y. Enantioselective Phosphine‐Catalyzed Formal [4 + 4] Annulation of α,β-Unsaturated Imines and Allene Ketones: Construction of EightMembered Rings. Angew. Chem. Int. Ed. 2017, 56, 14222–14226. (k) Yao, W.; Yu, Z.; Wen, S.; Ni, H.; Ullah, N.; Lan, Y.; Lu, Y. Chiral Phosphine-Mediated Intramolecular [3 + 2] Annulation: Enhanced Enantioselectivity by Achiral Brønsted Acid. Chem. Sci. 2017, 8, 5196–5200. (l) Wang, Z.; Xu, H.; Su, Q.; Hu, P.; Shao, P.-L.; He, Y.; Lu, Y. Enantioselective Synthesis of Tetrahydropyridines/Piperidines via Stepwise [4 + 2]/[2 + 2] Cyclizations. Org. Lett. 2017, 19, 3111– 3114. (m) Wang, Z.; Wang, T.; Yao, W.; Lu, Y. Phosphine-Catalyzed Enantioselective [4 + 2] Annulation of o-Quinone Methides with Allene Ketones. Org. Lett. 2017, 19, 4126–4129. (n) Ni, H.; Yu, Z.; Lan, Y.; Ullah, N.; Lu, Y. Catalyst-Controlled Regioselectivity in Phosphine Catalysis: The Synthesis of Spirocyclic Benzofuranones via Regiodivergent [3 + 2] Annulations of Aurones and an Allenoate. Chem. Sci. 2017, 8, 5699–5704. (o) Han, X.; Chan, W.-L.; Yao, W.; Wang, Y.; Lu, Y. Phosphine-mediated Highly Enantioselective Spirocyclization with Ketimines as Substrates. Angew. Chem. Int. Ed. 2016, 55, 6492–6496. (p) Wang, T.; Yu, Z.; Hoon, D. L.; Phee, C. Y.; Lan, Y.; Lu, Y. Regiodivergent Enantioselective γ-Additions of Oxazolones to 2,3-Butadienoates Catalyzed by Phosphines: Synthesis of α,α-Disubstituted α-Amino Acids and N,O-Acetal Derivatives. J.

Am. Chem. Soc. 2016, 138, 265–271. (10) For selected examples of natural products and biologically active molecules containing bicyclic pyran and hydrindane skeletons, see: (a) Sugano, M.; Sato, A.; Iijima, Y.; Oshima, T.; Furuya, K.; Kuwano, H.; Hata, T.; Hanzawa, H. Phomactin A; A Novel PAF Nntagonist from a Marine Fungus Phoma sp. J. Am. Chem. Soc. 1991, 113, 5463–5464. (b) Takahashi, C.; Numata, A.; Yamada, T.; Minoura, K.; Enomoto, S.; Konishi, K.; Nakai, M.; Matsuda, C.; Nomoto, K. Penostatins, Novel Cytotoxic Metabolites from a Penicillium Species Separated from a Green Alga. Tetrahedron Lett. 1996, 37, 655–658. (c) Sugimoto, Y.; Inanaga, S.; Kato, M.; Shimizu, T.; Hakoshima, T.; Isogai, A. Dechloroacutumine from Cultured Roots of Menispermum Dauricum. Phytochemistry 1998, 49, 1293– 1297. (d) Kikuchi, H.; Miyagawa, Y.; Sahashi, Y.; Inatomi, S.; Haganuma, A.; Nakahataa, N.; Oshima, Y. Novel Trichothecanes, Paecilomycine A, B, and C, Isolated from Entomopathogenic Fungus, Paecilomyces Tenuipes. Tetrahedron Lett. 2004, 45, 6225–6228. (e) Lenta, B. N.; Chouna, J. R.; Nkeng-Efouet, P. A.; Sewald, N. Endiandric Acid Derivatives and Other Constituents of Plants from the Genera Beilschmiedia and Endiandra. Biomolecules 2015, 5, 910– 942. (11) The data of crystals (CCDC 1854837 for 2e and 1550577 for 4m) can be obtained free of charge from The Cambridge Crystallographic Data Center via www.ccdc.cam.ac.uk/data_request/cif.

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