Catalytic Asymmetric Cascade Cyclization for Constructing Three

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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Catalytic Asymmetric Cascade Cyclization for Constructing Three Contiguous Stereocenters in Pyrrolobenzodiazepine-Based Cyclopentanones Zhao Wei,†,‡ Jinlong Zhang,† Huameng Yang,† and Gaoxi Jiang*,† †

State Key Laboratory for Oxo Synthesis and Selective Oxidation, Center for Excellence in Molecular Synthesis, Suzhou Research Institute of LICP, Lanzhou Institute of Chemical Physics (LICP), Chinese Academy of Sciences, Lanzhou 730000, P. R. China ‡ University of Chinese Academy of Sciences, Beijing 100049, P. R. China Org. Lett. Downloaded from pubs.acs.org by IDAHO STATE UNIV on 04/01/19. For personal use only.

S Supporting Information *

ABSTRACT: A chiral Brønsted acid catalyzed highly enantioand diastereoselective cascade cyclization has been developed to streamline the synthesis of valuable multifunctionalized enantioenriched cyclopenta[f ]pyrrolo[1,2-d][1,4]diazepinones bearing three contiguous stereocenters in high yields with excellent control of stereochemistry from a wide range of both readily available 2-furylcarbinols and (1H-pyrrol-1-yl)anilines, which represents the first asymmetric intramolecular conjugate addition of α,β-unsaturated cycloketones with inert N-substituted pyrroles as well as the first enantioselective aza-piancatelli rearrangement/Friedel−Crafts alkylation cascade reaction.

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hindrance, difficulties of the control of stereoselectivity, and unavoidable multistep synthetic dilemmas. As an important family of nitrogen-containing polycyclic compounds, benzodiazepines are quite ubiquitous in medicine chemistry since they are always vital for bioactivity in antianxiety, anticonvulsant, sedative, antidepressant, antiinflammatory, and hypnotic agents.5 Particularly, pyrrolobenzodiazepines are orally active arginine vasopressin (AVP, V1 and V2; Figure 1) receptor antagonists as well as have other potential curative effects for nephrotic syndrome, liver cirrhosis, hyponatremia, and congestive heart failure.6 Consequently, the development of practical methods toward such molecule skeletons is highly desirable. Cascade reaction is one of the most effective technologies to enable expeditious synthesis of complex molecules due to the innately high step economy and synthetic efficiency.7 Recently, Reddy’s group8a reported a Lewis acid catalyzed racemic cascade cyclization between 2-furylcarbinols and (1H-pyrrol-1-yl)anilines, which provides a simple and valuable access to such structures with concomitant formation of cyclopenanones bearing three contiguous stereocenters (Scheme 1, eq 1). However, development of the catalytic asymmetric process has remained unprecedented and very challenging, probably because of the weak reactivity between inert N-substituted pyrroles with α,βunsaturated ketones and the huge difficulties to control the stereoselectivity by traditional Lewis acid catalysis. Herein, we report a new strategy involving chiral Brønsted acid (CBA) catalysis to realize a highly enantio- and diastereoselective approach for this cascade cyclization (Scheme 1, eq 2).

ultifunctionalized cyclopentanones with contiguous multiple stereocenters are not only versatile precursors in organic transformations but also privileged structural motifs in natural products and pharmaceuticals.1 According to the table of “Top 200 Pharmaceutical Products by Retail Sales in 2016”, several bestselling medicines feature the crucial unit, such as Entecavir, Ticagrelor, and Bimatoprost (Figure 1).2

Figure 1. Important cyclopentane-based medicines with contiguous multiple stereocenters and orally bioactive pyrrolobenzodiazepines.

Given the immense applications and significance to pharmaceutics, a challenging study of interest is exploitation of a concise and efficient method to the unique structures.3 Nevertheless, in contrast with the triumphant strategies, for instance the powerful Diels−Alder reactions,4 to create contiguous multiple stereocenters in cyclohexanones, success in the case of cyclopentanones is very rare, reasonably due to its smaller alkyl ring leading to more congested steric © XXXX American Chemical Society

Received: February 27, 2019

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DOI: 10.1021/acs.orglett.9b00749 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

With this idea in mind, we initially selected 2-furylcarbinol 1a and 2-(1H-pyrrol-1-yl)aniline 2a as the model substrates to examine the catalytic activities of diverse CBA catalysts. As demonstrated in Table 1, A6 is the best catalyst and promoted

Scheme 1. Direct Synthesis of Pyrrolobenzodiazepine-Based Cyclopentanones Bearing Three Contiguous Stereocenters by Cascade Cyclization and Catalytic Addition of NSubstituted Pyrroles to Enones

Table 1. Optimization of the Reaction Conditions

Compared to unprotected pyrroles that can be activated by interaction with the N−H portion,9 the inert N-substituted pyrroles are more challenging to undergo asymmetric conjugate addition on account of the lack of an available N− H moiety. The reported samples are merely limited to “iminium-ion” catalysis with highly reactive α,β-unsaturated aldehydes (Scheme 1, 3a).10 The catalytic asymmetric addition to α,β-unsaturated ketones is very sparse. Besides the racemic catalytic process by Lewis acid In(OTf)3 catalysis via oxophilic activation to the carbonyl group (Scheme 1, 3b),8a recently, List and Coehlo realized the first asymmetric intermolecular addition of α,β-unsaturated linear ketones with indolizines involving CBA-catalysis by a monofunctional activation strategy via H-bond interaction.11 Considering the α,βunsaturated ketone is a versatile synthon for Michael addition reaction, the aza-Piancatelli reactions possess an inherent cascade tendency for synthesis of cyclopentane-based polycyclic compounds if another reactive nucleophilic group is reasonably implanted at the aniline in advance.12 Nevertheless, in fact, several common nucleophiles, including amino, phenol, and thiol, are completely inactive due to the interaction between such a nucleophile with the Brønsted acid catalyst to interrupt the second addition and the intrinsic inertness of unsaturated ketones.12a Such a cascade transformation is still undisclosed to date although it is of great significance to chemical and medicinal science. We anticipate that implantation of a pyrrole moiety into anilines might lead to a novel cascade reaction. We reasoned that (1) a pyrrole moiety could improve the nucleophilicity of aniline to accelerate the first cyclization, (2) the basic decrease of the nitrogen atom in aniline by a pyrrole substitute via an electron-withdrawing effect might prohibit the acid−base interaction that deactivates the Brønsted acid catalyst, and (3) the steric hindrance of nucleophilic pyrrole at the ortho-position should assist the control of enantioselectivity. We anticipated that CBA catalysis might execute the monofunctional activation via H-bond interaction to realize the first example of asymmetric intramolecular conjugate addition of α,β-unsaturated cycloketones with inert N-substituted pyrroles (Scheme 1, 3c) as well as the first enantioselective aza-Piancatelli rearrangement/ Friedel−Crafts alkylation cascade reaction (Scheme 1, eq 2).

entrya

CBA-cat.

solvent

yield (%)

er

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

A1 A2 A3 A4 A5 A6 A6 A6 A6 A6 A6 A6 A6 A6

CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CHCl3 ClCH2CH2Cl toluene benzene CHCl3 CHCl3 CHCl3 CHCl3

n.r. 35 n.r. 47 n.r. 44 58 52 35 41 68 71 81 92

− 60:40 − 60:40 − 87:13 90:10 83:17 87:13 86:14 90:10 92:8 92:8 94:6

a

Reaction conditions: 2-furylcarbinol 1a (0.1 mmol), 2-(1H-pyrrol-1yl)aniline 2a (0.10 mmol), CBA-cat. (5.0 mol %) in solvent (1.0 mL) at 25 °C for 16 h. Yield was determined by 1H NMR analysis of the crude reaction mixture. n.r. means no reaction. The er values were determined by chiral-phase HPLC. b2.0 mL of CHCl3 were used. c50 mg of 5 Å MS were added as additive. d10 mol % of A6 was used. e 0.15 mmol of 1a was used. Yield is that of the isolated product.

the cascade cyclization smoothly in CH2Cl2 at room temperature to provide the desired product 3aa with good results (entries 1−6). Solvent screening showed that CHCl3 was superior compared to other reaction media and the enantiomeric ratio (er) 90:10 was obtained (entries 6−10). Decreasing the concentration from 0.1 to 0.05 M increased the yield from 58% to 68% (entry 11). The addition of 5 Å molecular sieves (5 Å MS) improved the enantioselectivity of the product from er 90:10 to 92:8 (entry 12). Afterward, the catalyst loading increased from 5.0 mol % to 10 mol % and use of 1.5 equiv of 1a gave the excellent outcome of a 92% yield with er 94:6 (entries 13−14). Under the optimized reaction conditions, we next investigated the substrate scope with respect to both 2furylcarbinols and (1H-pyrrol-1-yl)anilines to evaluate the generality of the reaction. As shown in Scheme 2, for the reactions with 2a−b, a variety of 2-furylcarbinols 1 were very amenable to the reaction regardless of electric characteristics and the position of the substituents, resulting in the corresponding products 3aa−pa in 67−95% yields with er’s B

DOI: 10.1021/acs.orglett.9b00749 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 2. Scope with Respect to 2-Furylcarbinols and (1HPyrrol-1-yl)anilinesa

Scheme 3. Scope with Respect to (1H-Pyrrol-1-yl)anilines with 1oa

a

Reaction conditions: 1o (0.15 mmol,), 2 (0.1 mmol), A6 (10.0 mol %), 5 Å MS, in CHCl3 (2.0 mL) at 0 °C for 16 h. Yield is that of the isolated product. The er value of the products was determined by chiral-phase HPLC analysis. bAt 25 °C for 16 h. c1o (1.5 mmol, 0.396 g) and 2j (1.0 mmol, 0.226 g) were subjected to the reaction.

well tolerated and readily afforded the corresponding products 4of−oj in 88−98% yields with excellent enantioselectivities (er from 97:3 to 98:2). Treatment of 1o with 4-chloro-5-methyl (2c) and 4,5-dimethyl-2-(1H-pyrrol-1-yl)aniline (2k) under the optimal reaction conditions readily produced compounds 4oc and 4ok with excellent results (97−95% yields and 97.5:2.5 to 98.5:1.5 er). To further evaluate the practicability of the protocol, we performed a 1.0 mmol scale reaction.12a The transformation of 1o with 2j could take place well without any loss of yield and stereoselectivity. Accordingly, 4oj was isolated in 0.425 g (90% yield) with er 97.5:2.5 by the subjection of 0.396 g of 1o and 0.226 g of 2j to the standard reaction conditions. In order to confirm our hypothesis (Scheme 1, eq 2) for this cascade cyclization, control reactions for the intermediate were executed. As demonstrated in Scheme 4, the reaction of 1o and 2j in the presence of A6 (10.0 mol %) for only 5 min under −20 °C assembled the key intermediate cyclopentenone 5 in about 30% yield with er 97.5:2.5 (3:1 dr), concomitantly leading to the final ring-closure product 4oj in about 10% yield without any loss of enantioselectivity (er 97.5:2.5) but with

a

Reaction conditions: 2-furylcarbinol 1a−p (0.15 mmol), 2a−b (0.1 mmol), A6 (10.0 mol %), 50 mg of 5 Å MS, in CHCl3 (2.0 mL) at 25 °C for 16 h. Presented yield is that of the isolated product. The er values of the products were determined by chiral-phase HPLC analysis.

from 88:12 to 98.5:1.5 and all with more than 20:1 diastereoselectivities (d.r.). In general, substrates bearing an electron-donating group such as −OMe gave somewhat better enantioselectivity (1f, 1k, 1l, and 1o), reasonably due to the stronger H-bond interaction between cyclopentenone and the CBA catalyst. With furan-2-yl(thiophen-3-yl)methanol 1p as the substrate, the reaction gave rise to the desired product 3pa in good yield (89%) and moderate enantioselectivity (er 92.5:7.5). Using the indole substrate 2b instead of pyrroles, the reaction with 1o was completely interrupted before the second cyclization and led to 3ob with excellent results (94% yield, er 98.5:1.5), reasonably due to the weak nucleophilicity at the indole 2-position. We next examined the compatibility of our CBA-catalyzed cascade cyclization with kinds of 2-(1H-pyrrol-1-yl)anilines. As demonstrated in Scheme 3, with the furylcarbinol 1o, the cascade transformation worked well for a wide range of 2-(1Hpyrrol-1-yl)anilines. The challenging substrate 2-methyl-6(1H-pyrrol-1-yl)aniline 2e was also applicable to this catalytic cascade cyclization and delivered 4oe in 75% yield with er 93.5:6.5, probably due to the steric hindrance. 2f−j bearing either an electron-donating group (−Me and −OMe) or an electron-withdrawing group (−Cl, −Br, and −CF3) at the meta- and para-position of the benzyl rings were found to be

Scheme 4. Investigation of Intermediates

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DOI: 10.1021/acs.orglett.9b00749 Org. Lett. XXXX, XXX, XXX−XXX

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much higher diastereoselectivity (>20/1 dr) which indicates that there might be a synergistic effect in the cyclization sequence. The next intramolecular Friedel−Crafts-type conjugate addition of 5 could be catalyzed by the achiral Brønsted acid rac-cat-7, and its stereoselectivity was completely delivered into the product although the reaction temperature was up to 120 °C. The same stereoselectivity was also obtained when the opposite enantiomeric catalyst ent-A6 was used for the second cyclization under the standard reaction conditions. Additionally, treatment of 5 to the standard reaction conditions (Table 1, entry 14) also afforded the same results as ent-A6 catalysis. These results along with previous observations13 strongly support our initially anticipated reaction sequence with high efficiency. Given the great potential and significance for the exploitation of medicine candidates, new structure assembly based on multifunctionalized cyclopentanones and pyrrolobenzodiazepines represents the most effective and direct strategy for the purpose. Particularly, enantioenriched molecules could always enhance bioactivity. Therefore, it is worthwhile to apply our new method to the synthesis of human NK1 (hNK1) antagonist analogues.1d,14 Consequently, as shown in Scheme 5, the reduction of 4oj by NaBH4 in the

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Gaoxi Jiang: 0000-0003-1555-1107 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Financial support from the Natural Science Foundation of Jiangsu Province (Grant No. BK20160396) is gratefully acknowledged.

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REFERENCES

(1) (a) Harre, M.; Raddatz, P.; Walenta, R.; Winterfeldt, E. 4-Oxo-2cyclopentenyl AcetateA Synthetic Intermediate. Angew. Chem., Int. Ed. Engl. 1982, 21, 480−492. (b) Das, S.; Chandrasekhar, S.; Yadav, J. S.; Grée, R. Recent Developments in the Synthesis of Prostaglandins and Analogues. Chem. Rev. 2007, 107, 3286−3377. (c) Kurteva, V. B.; Afonso, C. A. M. Synthesis of Cyclopentitols by Ring-Closing Approaches. Chem. Rev. 2009, 109, 6809−6857. (d) Kuethe, J. T. The Art of Process Chemistry: Chapter 7, Cyclopentane-Based NK1 Receptor Antagonist; Yasuda, N., Ed.; Wiley-VCH Verlag GmbH & Co. KGaA: 2011. (e) Hanessian, S.; Vakiti, R. R.; Dorich, S.; Banerjee, S.; Deschênes-Simard, B. Total Synthesis of Pactamycin and Pactamycate: A Detailed Account. J. Org. Chem. 2012, 77, 9458−9472. (f) Schmidts, V.; Fredersdorf, M.; Lübken, T.; Porzel, A.; Arnold, N.; Wessjohann, L.; Thiele, C. M. RDC-Based Determination of the Relative Configuration of the Fungicidal Cyclopentenone 4,6Diacetylhygrophorone A12. J. Nat. Prod. 2013, 76, 839−844. (g) Volla, C. M. R.; Atodiresei, I.; Rueping, M. Catalytic C−C Bond-Forming Multi-Component Cascade or Domino Reactions: Pushing the Boundaries of Complexity in Asymmetric Organocatalysis. Chem. Rev. 2014, 114, 2390−2431. (h) D’yakonov, V. A.; Trapeznikova, O. A.; de Meijere, A.; Dzhemilev, U. M. Metal Complex Catalysis in the Synthesis of Spirocarbocycles. Chem. Rev. 2014, 114, 5775−5814. (i) Simeonov, S. P.; Nunes, J. P. M.; Guerra, K.; Kurteva, V. B.; Afonso, C. A. M. Synthesis of Chiral Cyclopentenones. Chem. Rev. 2016, 116, 5744−5893. (j) Wang, H.; Wang, L.; Li, Y.; Zhang, X.; Tang, P. Collective Synthesis of Schilancidilactones A, B and Schilancitrilactones A, B, C, 20-epiSchilancitrilactone A. Chin. J. Chem. 2019, 37, 255−268. (2) Compiled and Produced by the Njardarson Group (University of Arizona): Smith, D. T.; Delost, M. D.; Qureshi, H.; Njarđarson, J. T. See: https://njardarson.lab.arizona.edu/content/top-pharmaceuticalsposter. (3) (a) Bisacchi, G. S.; Chao, S. T.; Bachard, C.; Daris, J. P.; Innaimo, S.; Jacobs, G. A.; Kocy, O.; Lapointe, P.; Martel, A.; Merchant, Z.; Slusarchyk, W. A.; Sundeen, J. E.; Young, M. G.; Colonno, R.; Zahler, R. BMS-200475, a Novel Carbocyclic 2’deoxyguanosine Analog with Potent and Selective Anti-hepatitis B Virus Activity in Vitro. Bioorg. Med. Chem. Lett. 1997, 7, 127−132. (b) Dickmeiss, G.; De Sio, V.; Udmark, J.; Poulsen, T. B.; Marcos, V.; Jørgensen, K. A. Organocatalytic Asymmetric Desymmetrization− Fragmentation of Cyclic Ketones. Angew. Chem., Int. Ed. 2009, 48, 6650−6653. (c) Hoffman, T. J.; Carreira, E. M. Catalytic Asymmetric Intramolecular Hydroacylation with Rhodium/Phosphoramidite− Alkene Ligand Complexes. Angew. Chem., Int. Ed. 2011, 50, 10670− 10674. (d) Kumaraguru, T.; Babita, P.; Sheelu, G.; Lavanya, K.; Fadnavis, N. W. Synthesis of Enantiomerically Pure 4-Hydroxy-2cyclopentenones. Org. Process Res. Dev. 2013, 17, 1526−1530. (e) Deprés, J.-P.; Delair, P.; Poisson, J.-F.; Kanazawa, A.; Greene, A. E. Diverse Natural Products from Dichlorocyclobutanones: An Evolutionary Tale. Acc. Chem. Res. 2016, 49, 252−261. (f) Rajkumar, S.; Wang, J.; Wang, J.; Zheng, S.; Wang, D.; Ye, X.; Li, X.; Peng, Q.; Yang, X. Regioselective and Enantioselective Synthesis of β-Indolyl

Scheme 5. Enantioselective Synthesis of a Pyrrolobenzodiazepine-Based hNK1 Antagonist Analogue

presence of CeCl3·7H2O enabled the formation of alcohol 6 with good results. The following alkylation of the hydroxy group facilitated expediently the formation of hNK1 antagonist analogue 7 with high enantioselectivity. In summary, we developed a highly enantio- and diastereoselective cascade cyclization by CBA catalysis, which streamlines the synthesis of valuable enantioenriched cyclopenta[f ]pyrrolo[1,2-d][1,4]diazepinones bearing three contiguous stereocenters from a wide range of both readily available 2-furylcarbinols and (1H-pyrrol-1-yl)anilines. The reaction features many significant advantages such as mild reaction conditions, wide substituent tolerance, and good to excellent yields as well as chemo-, enantio-, and diastereoselectivities. Reasonable implantation of a pyrrole moiety into anilines realized the first example of asymmetric intramolecular conjugate addition of α,β-unsaturated cycloketones with inert N-substituted pyrroles as well as the first enantioselective azaPiancatelli rearrangement/Friedel−Crafts alkylation cascade reaction. Utilization of the method in the synthesis of hNK1 antagonist analogues highlighted the potential for the exploitation of pharmaceutically interesting molecules.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b00749. Experimental procedures and spectral data (PDF) D

DOI: 10.1021/acs.orglett.9b00749 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

2H-benzo[b][1,4]thiazine and Oxazine Derivatives. RSC Adv. 2012, 2, 10661−10666. (9) (a) Sheng, Y.-F.; Li, G.-Q.; Kang, Q.; Zhang, A.-J.; You, S.-L. Asymmetric Friedel−Crafts Reaction of 4,7-Dihydroindoles with Nitroolefins by Chiral Brønsted Acids under Low Catalyst Loading. Chem. - Eur. J. 2009, 15, 3351−3354. (b) Sheng, Y.-F.; Gu, Q.; Zhang, A.-J.; You, S.-L. Chiral Brønsted Acid-Catalyzed Asymmetric Friedel− Crafts Alkylation of Pyrroles with Nitroolefins. J. Org. Chem. 2009, 74, 6899−6901. (c) Trost, B. M.; Müller, C. Asymmetric Friedel−Crafts Alkylation of Pyrroles with Nitroalkenes Using a Dinuclear Zinc Catalyst. J. Am. Chem. Soc. 2008, 130, 2438−2439. (d) Singh, P. K.; Singh, V. K. Enantioselective Friedel−Crafts Alkylation of Pyrroles Catalyzed by PYBOX-DIPH-Zn(II) Complexes. Org. Lett. 2010, 12, 80−83. (e) Hua, Y.-Z.; Han, X.-W.; Yang, X.-C.; Song, X.; Wang, M.C.; Chang, J.-B. Enantioselective Friedel−Crafts Alkylation of Pyrrole with Chalcones Catalyzed by a Dinuclear Zinc Catalyst. J. Org. Chem. 2014, 79, 11690−11699. (f) Li, C.; Guo, F.; Xu, K.; Zhang, S.; Hu, Y.; Zha, Z.; Wang, Z. Copper-Catalyzed Enantioselective Friedel−Crafts Alkylation of Pyrrole with Isatins. Org. Lett. 2014, 16, 3192−3195. (g) Sun, J.; Hu, Y.; Li, Y.; Zhang, S.; Zha, Z.; Wang, Z. CopperCatalyzed Chemoselective and Enantioselective Friedel−Crafts 1,2Addition of Pyrrole with β,γ-Unsaturated α-Ketoesters. J. Org. Chem. 2017, 82, 5102−5110. (10) (a) Paras, N. A.; MacMillan, D. W. C. New Strategies in Organic Catalysis: The First Enantioselective Organocatalytic Friedel−Crafts Alkylation. J. Am. Chem. Soc. 2001, 123, 4370−4371. (b) Li, G.; Rowland, G. B.; Rowland, E. B.; Antilla, J. C. Organocatalytic Enantioselective Friedel−Crafts Reaction of Pyrrole Derivatives with Imines. Org. Lett. 2007, 9, 4065−4068. (11) Correia, J. T. M.; List, B.; Coelho, F. Catalytic Asymmetric Conjugate Addition of Indolizines to α,β-Unsaturated Ketones. Angew. Chem., Int. Ed. 2017, 56, 7967−7970. (12) (a) Cai, Y.; Tang, Y.; Atodiresei, I.; Rueping, M. Catalytic Asymmetric Piancatelli Rearrangement: Brønsted Acid Catalyzed 4π Electrocyclization for the Synthesis of Multisubstituted Cyclopentenones. Angew. Chem., Int. Ed. 2016, 55, 14126−14130. (b) Li, H.; Tong, R.; Sun, J. Catalytic Enantioselective Aza-Piancatelli Rearrangement. Angew. Chem., Int. Ed. 2016, 55, 15125−15128. (c) Gade, A. B.; Patil, N. T. Catalytic Enantioselective Aza-Piancatelli Rearrangement. Synlett 2017, 28, 1096−1100. (13) (a) Li, S.-W.; Batey, R. A. Mild Lanthanide(III) Catalyzed Formation of 4,5-Diaminocyclopent-2-enones from 2-Furaldehyde and Secondary Amines: a Domino Condensation/Ring-Opening/ Electrocyclization Process. Chem. Commun. 2007, 3759−3761. (b) Wenz, D. R.; de Alaniz, J. R. Aza-Piancatelli Rearrangement Initiated by Ring Opening of Donor−Acceptor Cyclopropanes. Org. Lett. 2013, 15, 3250−3253. (c) Chung, R.; Yu, D.; Thai, V. T.; Jones, A. F.; Veits, G. K.; de Alaniz, J. R.; Hein, J. E. Tandem Reaction Progress Analysis as a Means for Dissecting Catalytic Reactions: Application to the Aza-Piancatelli Rearrangement. ACS Catal. 2015, 5, 4579−4585. (14) (a) Finke, P. E.; Meurer, L. C.; Levorse, D. A.; Mills, S. G.; MacCoss, M.; Sadowski, S.; Cascieri, M. A.; Tsao, K.-L.; Chicchi, G. G.; Metzger, J. M.; MacIntyre, D. E. Cyclopentane-Based Human NK1 Antagonists. Part 1: Discovery and Initial SAR. Bioorg. Med. Chem. Lett. 2006, 16, 4497−4503. (b) Meurer, L. C.; Finke, P. E.; Owens, K. A.; Tsou, N. N.; Ball, R. G.; Mills, S. G.; MacCoss, M.; Sadowski, S.; Cascieri, M. A.; Tsao, K.-L.; Chicchi, G. G.; Egger, L. A.; Luell, S.; Metzger, J. M.; MacIntyre, D. E.; Rupniak, N. M. J.; Williamse, A. R.; Hargreavese, R. J. Cyclopentane-Based Human NK1 Antagonists. Part 2: Development of Potent, Orally Active, WaterSoluble Derivatives. Bioorg. Med. Chem. Lett. 2006, 16, 4504−4511. (c) Kuethe, J. T.; Marcoux, J.-F.; Wong, A.; Wu, J.; Hillier, M. C.; Dormer, P. G.; Davies, I. W.; Hughes, D. L. Stereoselective Preparation of a Cyclopentane-Based NK1 Receptor Antagonist Bearing an Unsymmetrically Substituted Sec−Sec Ether. J. Org. Chem. 2006, 71, 7378−7390.

Cyclopentenamides by Chiral Anion Catalysis. Angew. Chem., Int. Ed. 2018, 57, 13489−13494. (g) Hu, F.; Zhou, Q.; Cao, F.; Chu, W.-D.; He, L.; Liu, Q.-Z. Enantioselective Formal [4 + 1] Cycloaddition of Diazoarylacetates and the Danishefsky’s Diene: Stereoselective Synthesis of (−)-1,13-Herbertenediol. J. Org. Chem. 2018, 83, 12806−12814. (h) Farley, C. M.; Zhou, Y.-Y.; Banka, N.; Uyeda, C. Catalytic Cyclooligomerization of Enones with Three Methylene Equivalents. J. Am. Chem. Soc. 2018, 140, 12710−12714. (i) Tao, D. J.; Slutskyy, Y.; Muuronen, M.; Le, A.; Kohler, P.; Overman, L. E. Total Synthesis of (−)-Chromodorolide B By a ComputationallyGuided Radical Addition/Cyclization Fragmentation Cascade. J. Am. Chem. Soc. 2018, 140, 3091−3102. (4) (a) Nicolaou, K. C.; Snyder, S. A.; Montagnon, T.; Vassilikogiannakis, G. The Diels−Alder Reaction in Total Synthesis. Angew. Chem., Int. Ed. 2002, 41, 1668−1698. (b) Takao, K.; Munakata, R.; Tadano, K. Recent Advances in Natural Product Synthesis by Using Intramolecular Diels−Alder Reactions. Chem. Rev. 2005, 105, 4779−807. (c) Heintzelman, G. R.; Meigh, I. R.; Mahajan, Y. R.; Weinreb, S. W. Diels-Alder Reactions of Imino Dienophiles. Org. React. 2005, 65, 141−599. (d) Erkkilä, A.; Majander, I.; Pihko, P. M. Iminium Catalysis. Chem. Rev. 2007, 107, 5416−5470. (e) Reymond, S.; Cossy, J. Copper-Catalyzed Diels−Alder Reactions. Chem. Rev. 2008, 108, 5359−5406. (f) Jiang, X.; Wang, R. Recent Developments in Catalytic Asymmetric Inverse-Electron-Demand Diels−Alder Reaction. Chem. Rev. 2013, 113, 5515−5546. (5) (a) Schutz, H. Benzodiazepines; Springer: Heidelberg, 1982. (b) Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.; Freidinger, R. M.; Whitter, W. L.; Lundell, G. F.; Veber, D. F.; Anderson, P. S.; Chang, R. S. L.; Lotti, V. J.; Cerino, D. J.; Chen, T. B.; Kling, P. J.; Kunkel, K. A.; Springer, J. P.; Hirshfield, J. Methods for Drug Discovery: Development of Potent, Selective, Orally Effective Cholecystokinin Antagonists. J. Med. Chem. 1988, 31, 2235−2246. (c) Fryer, R. I.; Taylor, E. C.; Bicyclic Diazapines. In The Chemistry of Heterocyclic Compounds; Wiley: New York, 1991; Vol. 50, ch II. (d) Horton, D. A.; Bourne, G. T.; Smythe, M. L. The Combinatorial Synthesis of Bicyclic Privileged Structures or Privileged Substructures. Chem. Rev. 2003, 103, 893−930. (e) Wang, L.-Z.; Li, X.-Q.; An, Y.-S. 1,5-Benzodiazepine Derivatives as Potential Antimicrobial Agents: Design, Synthesis, Biological Evaluation, and Structure−Activity Relationships. Org. Biomol. Chem. 2015, 13, 5497−5509. (6) (a) Trybulski, E. J. In Annual Reports in Medicinal Chemistry; Doherty, A. M., Ed.; Academic Press: San Diego, 2001; Vol. 36, p 159. (b) Wong, L. L.; Verbalis, J. G. Vasopressin V2 Receptor Antagonists. Cardiovasc. Res. 2001, 51, 391−402. (c) Palm, C.; Reimann, D.; Gross, P. The role of V2 Vasopressin Antagonists in Hyponatremia. Cardiovasc. Res. 2001, 51, 403−408. (d) Sum, F.-W.; Dusza, J.; Santos, E. D.; Grosu, G.; Reich, M.; Du, X.; Albright, J. D.; Chan, P.; Coupet, J.; Ru, X.; Mazandarani, H.; Saunders, T. Structure−activity Study of Novel Tricyclic Benzazepine Arginine Vasopressin Antagonists. Bioorg. Med. Chem. Lett. 2003, 13, 2195−2198. (7) (a) Tietze, L.-F.; Brasche, G.; Gericke, K. M. Domino Reactions in Organic Synthesis; Wiley-VCH: Weinheim, 2006. (b) Muller, T. J. J. Metal Catalysed Cascade Reactions; Wiley-VCH: Weinheim, 2006. (c) Enders, D.; Grondal, C.; Hü ttl, M. R. M. Asymmetric Organocatalytic Domino Reaction. Angew. Chem., Int. Ed. 2007, 46, 1570−1581. (d) Jones, A. C.; May, J. A.; Sarpong, R.; Stoltz, B. M. Toward a Symphony of Reactivity: Cascades Involving Catalysis and Sigmatropic Rearrangements. Angew. Chem., Int. Ed. 2014, 53, 2556− 2591. (e) Xu, P.-F.; Wang, W. Catalytic Cascade Reactions; John Wiley & Sons, Inc.: 2014. (8) (a) Reddy, B. V. S.; Reddy, Y. V.; Singarapu, K. K. Sequential Aza-Piancatelli Rearrangement/Friedel−Crafts Alkylation for the Synthesis of Pyrrolo[1,2-d]benzodiazepine derivatives. Org. Biomol. Chem. 2016, 14, 1111−1116. (b) Reddy, B. V. S.; Reddy, Y. V.; Lakshumma, P. S.; Narasimhulu, G.; Yadav, J. S.; Sridhar, B.; Reddy, P. P.; Kunwar, A. C. In(OTf)3-Catalyzed Tandem Aza-Piancatelli Rearrangement/Michael Reaction for the Synthesis of 3,4-DihydroE

DOI: 10.1021/acs.orglett.9b00749 Org. Lett. XXXX, XXX, XXX−XXX