Synthesis of Chiral, Densely Substituted Pyrrolidones via Phosphine

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

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Synthesis of Chiral, Densely Substituted Pyrrolidones via PhosphineCatalyzed Cycloisomerization Barry M. Trost,* Elumalai Gnanamani, Chao-I Joey Hung, and Christopher A. Kalnmals Department of Chemistry, Stanford University, Stanford, California 94305, United States

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S Supporting Information *

ABSTRACT: Densely substituted chiral pyrrolidones are synthesized via phosphine-catalyzed cycloisomerization of enantioenriched β-amino ynones, which are prepared in a single step using a highly enantioselective Zn-ProPhenolcatalyzed Mannich reaction. The exocyclic alkenes in the cyclization products provide versatile handles for further transformations and typically form with good E/Z selectivity. This cycloisomerization method can be performed in streamlined fashion, without purification of the intermediate Mannich adduct, and extends to anthranilic acid based scaffolds in addition to ProPhenol-derived Mannich adducts.

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the preparation of fully substituted chiral pyrrolidines remains an important challenge in organic chemistry. Here, we present a method for the synthesis of chiral, densely substituted pyrrolidine derivatives that relies on the phosphine-catalyzed isomerization of easily accessible amino ynones. Previously, we reported that conjugated ynones 1 undergo redox isomerization to the corresponding 1,3-dienones 2 in the presence of catalytic phosphine and acetic acid (Scheme 2a).10 Later, we and others developed related phosphine-catalyzed methods for the formation of tetrahydrofurans.11a,b When we applied our standard redox isomerization conditions to Mannich adduct 3 bearing an alkyl chain, we were pleased to obtain the expected dienone 4 in 60% yield, along with a smaller amount of cycloisomerization product 5 (Scheme 2b). We were intrigued by this result due to its complementarity to transition-metal-catalyzed processes; whereas gold and platinum promote 5-endo11c,d and 6-endo12c cyclizations of aminoynones (Scheme 2c), interestingly our transformation selectively affords the 5-exo products (Scheme 2d). We hypothesized that this new cycloisomerization pathway would predominate if the redox isomerization manifold was blocked. Indeed, when phenyl-substituted amino ynone 8a was treated with catalytic dppp, complete conversion was observed and pyrrolidone 9a/a′ was obtained as the sole product with 2.4:1 crude E/Z selectivity (Scheme 3). To further improve the geometrical selectivity, we evaluated a variety of other bidentate phosphines. We first investigated the effect of the tether length and found that dppe and dppb gave similar results to dppp, whereas dppm gave lower conversion and geometrical selectivity. Incomplete conversion was also observed with dppf, although the crude E/Z selectivity improved to 4.5:1. Fortunately, geometrical selectivity increased when monodentate phosphines were used, with

eavily substituted pyrrolidines are common motifs in both pharmaceuticals and natural products.1 For example, (+)-preussin has antifungal,2 antitumor,3 and antiviral activity,4 and the radicamines function as α-glucosidase inhibitors.5 Anisomycin exhibits antifungal activity by inhibiting DNA and protein synthesis, and can also disrupt memory consolidation (Scheme 1).6 Furthermore, enantioenriched pyrrolidines are often used to synthesize ligands and organocatalysts, which makes them valuable building blocks in asymmetric catalysis.7 Scheme 1. Bioactive Molecules With Substituted Pyrrolidines

Given the prevalence and broad utility of pyrrolidines in organic synthesis, developing new methods for their asymmetric synthesis is an important goal. Many existing methods for the enantioselective preparation of pyrrolidines rely on the use of proline-derived starting materials.8 While this chiral pool approach is useful, the groups present in the starting materials dictate the substitution patterns of the products. A variety of other approaches for the de novo synthesis of chiral pyrrolidines have also been reported,9 but © XXXX American Chemical Society

Received: February 7, 2019

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DOI: 10.1021/acs.orglett.9b00496 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

Scheme 4. Scope of the Reaction with Various Iminesa

Scheme 2. Summary of Prior and Current Work

a

Reaction conditions: 1 equiv of ynone, 1.1 equiv of imine, 10 mol % of Zn-ProPhenol, at rt in THF (0.3 M) for 12 h, followed by chromatography; then 10 mol % of PPh3, 40 mol % of AcOH in toluene (0.3 M) for 3 h at 75 °C. Yields are given for the cycloisomerization step. bMannich reaction was conducted at 4 °C for 24 h. cMePPh2 was used instead of PPh3.

Scheme 3. Optimization of Phosphine Ligands

pyrrolidones 9a−9c in 79−84% yield with excellent enantioselectivity. Notably, ortho-substituted phenyl and heteroaryl substituents were well tolerated, giving rise to 9d and 9e in 76% and 69% yield, respectively. To unambiguously establish the alkene geometry of our products, we obtained a crystal structure of racemic 2-furyl pyrrolidone 9e (CCDC No. 1875207) and determined the olefin configuration to be E. The geometry of all other products was assigned by analogy. N-Cbz-protected Mannich adducts were also viable substrates for this transformation; pyrrolidones 9f and 9g were obtained with excellent enantioselectivity in yields similar to the analogous N-Boc compounds. As before, orthosubstitution was not problematic and pyrrolidone 9h was obtained in 72% yield and 94% eea notable result given that such cinnamate-bearing Mannich adducts are useful precursors to isoindoline derivatives.13 Under our standard conditions, a Mannich adduct from an aliphatic imine required 24 h to complete conversion. Fortunately, the use of methyldiphenylphosphine as a more nucleophilic catalyst gave full conversion in 2 h, affording cyclized product 9i in 79% yield and 92% ee. Furthermore, a vinyl imine derived Mannich adduct was cyclized to 9j in 68% yield with 87% ee. By changing the substitution pattern on the nucleophile in the ProPhenol step, it was also possible to generate spirocycles and pyrrolidones with an additional stereocenter at the 4position (Scheme 5). This is noteworthy, given that spirocyclic compounds often have better pharmacokinetic properties than analogous fused ring compounds and are relatively underexplored.14 Exchanging the gem-dimethyl substitution in 7a for a cyclohexane resulted in slightly lower E/Z selectivity, and

methyldiphenylphosphine giving 9 in full conversion and a slightly improved 3:1 E/Z ratio. With triphenylphosphine, crude E/Z selectivity increased further to 9:1. Attempts to further increase the olefin ratio by using ortho-substituted and electron-rich triarylphosphines were unsuccessful and resulted in no reaction, presumably due to steric crowding around the phosphorus center. With optimized conditions in hand, we set out to explore the scope of the isomerization reaction (Scheme 4). The required β-amino ynone substrates were synthesized via a ZnProPhenol-catalyzed Mannich reaction between aldimines and alkynones and were obtained in excellent yields and enantioselectivities (70−99% ee).12 After isolation, the Mannich adducts were readily cycloisomerized to pyrrolidones 9, which were typically obtained in excellent yields as mixtures of easily separable olefin isomers. Importantly, the enantiopurity of the Mannich adducts is not eroded during the cycloisomerization step. First, we investigated the scope of imines 6 with gemdimethyl ynone 7a. Neutral and electron-rich aromatic rings all gave similar results in the cyclization step, affording B


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(Scheme 6). Upon completion of the ProPhenol step, triphenylphosphine and AcOH in toluene were added and

Scheme 5. Reaction Scope with Spirocycles and Unsymmetrically Substituted Ynonesa

Scheme 6. Streamlined Protocola

a

Reaction conditions: 1 equiv of ynone, 1.1 equiv of imine, 10 mol % of Zn-ProPhenol, at rt in THF (0.3 M) for 12 h, followed by filtration through a short plug of Celite, removal of solvent, addition of 10 mol % of PPh3 and 40 mol % of AcOH in toluene (0.3 M), then stirring at 75 °C for 3 h. Yields are given for the two-step sequence.

the reaction was stirred at 75 °C. To our delight, this streamlined procedure afforded the cyclization products with comparable yields and selectivities to the two-step synthesis, as exemplified by the result obtained for pyrrolidone 9a (cf. Scheme 4). Furthermore, this compound could be prepared on 1 mmol scale with no erosion of yield or selectivity. This streamlined protocol extended well to other substrates, and tolyl-substituted ynone was transformed into pyrrolidone 9t in 73% yield. Likewise, spirocyclic cyclobutane 9u and 2-thienyl 9v were isolated in 66% yield and 63% yield respectively, both with 91% ee. In addition to the excellent substrate scope exhibited with regards to ProPhenol-derived Mannich adducts, we were pleased to find that our cycloisomerization method applies to other amino ynone scaffolds as well (Scheme 7). Thus, when anthranilic acid derived 10a (n = 0) was subjected to our previously optimized conditions, 3-oxindole derivative 11a formed in 99% yield and >20:1 E/Z selectivity.

a

Reaction conditions: 1 equiv of ynone, 1.1 equiv of imine, 10 mol % of Zn-ProPhenol, at rt in THF (0.3 M) for 12 h, followed by chromatography; then 10 mol % of PPh3, 40 mol % of AcOH in toluene (0.3 M) for 3 h at 75 °C. Yields are given for the cycloisomerization step. bAfter recrystallization. cCrude E/Z ratio of 1.3:1 determined by 1H NMR and reaction carried out for 8 h at 75 °C.

pyrrolidone 9k was obtained in 71% yield as a 4:1 mixture of separable E/Z isomers. It was also possible to synthesize heterocyclic spirocycles, such as tetrahydropyran 9l (86% yield, 92% ee) and N-Boc piperidine 9m (66% yield, 82% ee), using our methodology. The latter (9m) bears a resemblance to several biologically active molecules15 and could be obtained as a single olefin isomer in >99% ee by recrystallization. To highlight the selectivity of our ProPhenol-catalyzed Mannich reaction, several Mannich products were prepared from unsymmetrically substituted ynones in excellent enantioand diastereoselectivity and then cyclized under our standard reaction conditions to give products bearing a quaternary stereocenter. In this way, pyrrolidones bearing benzyl (9n), isobutyl (9o), and isobutenyl (9p) substituents at the 4position were prepared in excellent yield, E/Z selectivity, and >20:1 diastereoselectivity. In addition, an N-Cbz-protected Mannich adduct was a viable cyclization substrate, and pyrrolidone 9q bearing a quaternary stereocenter formed in 75% yield, 7:1 E/Z selectivity, and >20:1 diastereoselectivity. Our cyclization protocol also tolerates other aryl substituents. For example, a tolyl-bearing pyrrolidone (9r) was prepared in 72% yield and 98% ee. A polyaromatic ynone was also a viable substrate, affording phenanthryl pyrrolidone 9s in 79% overall yield with excellent enantioselectivity, albeit with reduced diastereoselectivity. To further highlight the utility of our Mannich-cycloisomerization sequence, we demonstrated that this transformation could be carried out in a streamlined fashion

Scheme 7. Synthesis of Oxindole and Isoquinolone Derivativesa

a

Reaction conditions: ynone 10, 10 mol % of PPh3, 40 mol % of AcOH in toluene (0.3 M) for 3 h at 75 °C. bMePPh2 was used instead of PPh3. C


Letter

Organic Letters Similarly excellent results were obtained with p-tolyl (10b) and cyclopropyl (10c) ynones, with the latter giving a particularly rapid reaction. A sterically hindered tert-butyl ynone could also be isomerized when MePPh2 was used as the catalyst, and 11d was obtained in 93% yield. Our methodology also extends to the synthesis of sixmembered rings (n = 1) as evidenced by isoquinolone 11e, which was obtained in 95% yield with excellent geometrical selectivity. To highlight the synthetic utility of our densely substituted pyrrolidone products, we performed several derivatization reactions that take advantage of the unique juxtaposition of functionality present in these compounds (Scheme 8). Luche reduction of the ketone 9a was highly

piperidones is reported. This cycloisomerization method applies to a variety of scaffolds, including chiral ynones synthesized via ProPhenol-catalyzed Mannich reactions and achiral ynones derived from anthranilic acid. The resultant heterocycles bear substituents at every position on the ring including a ketone and a stereodefined exocyclic olefin, both of which are useful handles for further elaboration. Furthermore, a streamlined Mannich-cyclization protocol that rapidly generates chiral, structurally complex pyrrolidones from simple aldimine and ynone starting materials is demonstrated. Given the prevalence of nitrogen heterocycles in pharmaceuticals and natural products and the challenges associated with accessing densely substituted ring systems, this practical, atom-economic method should have wide utility for the synthesis of bioactive molecules.

Scheme 8. Derivatization Reactions

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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.9b00496. Experimental procedures and spectroscopic data (PDF) Accession Codes

CCDC 1875207 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

selective and generated alcohol 12 as a single diastereomer in 86% yield. Hydrogenation of the enamide alkene was similarly selective, and saturated pyrrolidone 13 was obtained in 83% yield and 12:1 dr. Finally, an azomethine (3 + 2) cycloaddition generated structurally intricate spirocycle 14 quantitatively based on recovered starting material and in 45% isolated yield. The stereochemistry of all the derivatization products was assigned by NOE. Mechanistically, we propose that the cycloisomerization occurs via an addition−elimination process, similar to that which we previously proposed for the redox isomerization of ynones to dienones (Scheme 9). First, the phosphine catalyst

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Barry M. Trost: 0000-0001-7369-9121 Elumalai Gnanamani: 0000-0003-3699-3350 Chao-I Joey Hung: 0000-0001-7569-5837 Christopher A. Kalnmals: 0000-0003-3233-290X

Scheme 9. Proposed Mechanism

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank Dr. Jana Maclaren (Stanford University) for X-ray crystallographic analysis. REFERENCES

(1) (a) Edmondson, S.; Danishefsky, S. J.; Sepp-Lorenzino, L.; Rosen, N. Total Synthesis of Spirotryprostatin A, Leading to the Discovery of Some Biologically Promising Analogues. J. Am. Chem. Soc. 1999, 121, 2147−2155. (b) Michael, J. P. Indolizidine and quinolizidine alkaloids. Nat. Prod. Rep. 2008, 25, 139−165. (c) Vitaku, E. D.; Smith, T.; Njardarson, J. T. Analysis of the Structural Diversity, Substitution Patterns, and Frequency of Nitrogen Heterocycles among U.S. FDA Approved Pharmaceuticals. J. Med. Chem. 2014, 57, 10257−10274. (d) Harwood, L. M.; Vickers, R. J. Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products; Padwa, A., Pearson, W., Eds.; Wiley: New York, 2002. (e) Slater, M. J.; Amphlett, E. M.; Andrews, D. M.; Bravi, G.; Burton, G.; Cheasty, A. G.; Corfield, J. A.; Ellis, M. R.; Fenwick, R. H.; Fernandes, S.; Guidetti, R.; Haigh, D.; Hartley, C. D.; Howes, P. D.; Jackson, D. L.; Jarvest, R. L.; Lovegrove, V. L. H.; Medhurst, K. J.;

adds to acid-activated ynone 8 in 1,4-fashion to generate allenol A. Nucleophilic addition of the nitrogen to the phosphonium-activated alkene generates enol B, which upon elimination of phosphine and a proton affords pyrrolidone 9 and regenerates the catalyst. In conclusion, a phosphine-catalyzed cycloisomerization that transforms β- and γ-amino ynones into pyrrolidones and D


Letter

Organic Letters Parry, N. R.; Price, H.; Shah, P.; Singh, O. M. P.; Stocker, R.; Thommes, P.; Wilkinson, C.; Wonacott, A. Optimization of Novel Acyl Pyrrolidine Inhibitors of Hepatitis C Virus RNA-Dependent RNA Polymerase Leading to a Development Candidate. J. Med. Chem. 2007, 50, 897−900. (f) Pyne, S. G.; Davis, A. S.; Gates, N. J.; Nicole, J.; Hartley, J. P.; Lindsay, K. B.; Machan, T.; Tang, M. Asymmetric Synthesis of Polyfunctionalized Pyrrolidines and Related Alkaloids. Synlett 2004, 2004, 2670−2680. (g) Pearson, W. H. In Studies in Natural Product Chemistry; Atta-Ur-Rahman, Ed.; Elsevier: New York, 1998; Vol. 1, p 323. (2) (a) Schwartz, R. E.; Liesch, J.; Hensens, O.; Zitano, L.; Honeycutt, S.; Garrity, G.; Fromtling, R. A.; Onishi, J.; Monaghan, R. J. A novel antifungal agent: fermentation, isolation, structural elucidation and biological properties. J. Antibiot. 1988, 41, 1774− 1779. (b) Schwartz, R. E.; Onishi, J. C.; Monaghan, R. L.; Liesch, J. M.; Hensens, O. D. Antifungal fermentation product and derivatives and compositions thereof U.S. Patent Appl. US 4847,284, 1989. (3) (a) Kasahara, K.; Yoshida, M.; Eishima, J.; Takesako, K.; Beppu, T.; Horinouchi, S. J. Identification of Preussin as a Selective Inhibitor for Cell Growth of the Fission Yeast ts Mutants Defective in Cdc2Regulatory Genes. J. Antibiot. 1997, 50, 267−269. (b) Achenbach, T. V.; Slater, E. P.; Brummerhop, H.; Bach, T.; Müller, R. Inhibition of Cyclin-Dependent Kinase Activity and Induction of Apoptosis by Preussin in Human Tumor Cells. Antimicrob. Agents Chemother. 2000, 44, 2794−2801. (c) Brummerhop, H.; Achenbach, T.; Müller, R.; Bach, T. Pyrrolidine compounds and their use for treating hyperproliferative diseases and tumor diseases. Patent Appl. WO 2001010832 A1, 2001. (4) Goss Kinzy, T.; Harger, J. W.; Carr-Schmid, A.; Kwon, J.; Shastry, M.; Justice, M.; Dinman, J. D. New Targets for Antivirals: The Ribosomal A-Site and the Factors That Interact with It. Virology 2002, 300, 60−70. (5) (a) Shibano, M.; Tsukamoto, D.; Masuda, A.; Tanaka, Y.; Kusano, G. Two New Pyrrolidine Alkaloids, Radicamines A and B, as Inhibitors of α-Glucosidase from Lobelia chinensis LOUR. Chem. Pharm. Bull. 2001, 49, 1362−1365. (b) Asano. Glycosidase inhibitors: update and perspectives on practical use. Glycobiology 2003, 13, 93R− 104R. (6) Zheng, X.; Cheng, Q.; Yao, F.; Wang, X.; Kong, L.; Cao, B.; Xu, M.; Lin, S.; Deng, Z.; Chooi, Y.-H.; You, D. Biosynthesis of the pyrrolidine protein synthesis inhibitor anisomycin involves novel gene ensemble and cryptic biosynthetic steps. Proc. Natl. Acad. Sci. U. S. A. 2017, 114, 4135−4140. (7) (a) Mukherjee, S.; Yang, W. J.; Hoffmann, S.; List, B. Asymmetric Enamine Catalysis. Chem. Rev. 2007, 107, 5471−5569. (b) Erkkilä, A.; Majander, I.; Pihko, P. M. Iminium Catalysis. Chem. Rev. 2007, 107, 5416−5470. (c) Berkessel, A.; Gröger, H. Asymmetric Organocatalysis; Wiley-VCH: Weinheim, 2005. (8) Bhat, C.; Tilve, S. G. Recent advances in the synthesis of naturally occurring pyrrolidines, pyrrolizidines and indolizidine alkaloids using proline as a unique chiral synthon. RSC Adv. 2014, 4, 5405−5452. (9) (a) For a list of references on pyrrolidine synthesis, see refs 4− 10 in: Vasse, J.-L.; Joosten, A.; Denhez, C.; Szymoniak, J. Stereoselective Synthesis of Pyrrolidines from N-Allyl Oxazolidines via Hydrozirconation−Cyclization. Org. Lett. 2005, 7, 4887−4889. (b) For a review on pyrrolidine synthesis, see: Pichon, M.; Figadère, B. Synthesis of 2,5-disubstituted pyrrolidines. Tetrahedron: Asymmetry 1996, 7, 927−964. (10) Trost, B. M.; Kazmaier, U. Internal redox catalyzed by triphenylphosphine. J. Am. Chem. Soc. 1992, 114, 7933−7935. (11) (a) Trost, B. M.; Li, C. J. Phosphine-Catalyzed IsomerizationAddition of Oxygen Nucleophiles to 2-Alkynoates. J. Am. Chem. Soc. 1994, 116, 10819−10820. (b) Silva, F.; Sawicki, M.; Gouverneur, V. Enantioselective Organocatalytic Aldol Reaction of Ynones and Its Synthetic Applications. Org. Lett. 2006, 8, 5417−5419. (c) Gouault, N.; Le Roch, M.; Cornee, C.; David, M.; Uriac, P. Synthesis of Substituted Pyr-rolin-4-ones from Amino Acids in Mild Conditions via a Gold-Catalyzed Approach. J. Org. Chem. 2009, 74, 5614−5617.

(d) Spina, R.; Col-acino, E.; Gabriele, B.; Salerno, G.; Martinez, J.; Lamaty, F. Synthesis of Pyrrolin-4-ones by Pt-Catalyzed Cycloisomerization in PEG under Microwaves. J. Org. Chem. 2013, 78, 2698−2702. (12) (a) Trost, B. M.; Hung, C.-I. Broad Spectrum Enolate Equivalent for Catalytic Chemo-, Diastereo-, and Enantioselective Addition to N-Boc Imines. J. Am. Chem. Soc. 2015, 137, 15940− 15946. (b) Trost, B. M.; Hung, C.-I.; Saget, T.; Gnanamani, E. Branched aldehydes as linchpins for the enantioselective and stereodivergent synthesis of 1,3-aminoalcohols featuring a quaternary stereocentre. Nature Catal 2018, 1, 523−530. (c) Trost, B. M.; Hung, C.-I.; Gnanamani, E. Tuning the Reactivity of Ketones through Unsaturation: Construction of Cyclic and Acyclic Quaternary Stereocenters via Zn-ProPhenol Catalyzed Mannich Reactions. ACS Catal. 2019, 9, 1549−1557. (13) Trost, B. M.; Gnanamani, E.; Hung, C. − I. Controlling Regioselectivity in the Enantioselective N-Alkylation of Indole Analogues Catalyzed by Dinuclear Zinc-ProPhenol. Angew. Chem., Int. Ed. 2017, 56, 10451−10456. (14) (a) Bindra, J. S.; Manske, R. H. F. The Alkaloids; Academic Press: New York, 1973; Vol. 14. (b) Marti, C.; Carreira, E. M. Construction of Spiro[pyrrolidine-3,3′-oxindoles] − Recent Applications to the Synthesis of Oxindole Alkaloids. Eur. J. Org. Chem. 2003, 2003, 2209. (c) Galliford, C. V.; Scheidt, K. A. PyrrolidinylSpirooxindole Natural Products as Inspirations for the Development of Potential Therapeutic Agents. Angew. Chem., Int. Ed. 2007, 46, 8748. (15) Smith, A. C.; Cabral, S.; Kung, D. W.; Rose, C. R.; Southers, J. A.; García-Irizarry, C. N.; Damon, D. B.; Bagley, S. W.; Griffith. The Synthesis of Methyl-Substituted Spirocyclic Piperidine-Azetidine (2,7Diazaspiro[3.5]nonane) and Spirocyclic Piperidine-Pyrrolidine (2,8Diazaspiro[4.5]decane) Ring Systems. J. Org. Chem. 2016, 81, 3509 and references cited therein .

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Synthesis of Chiral, Densely Substituted Pyrrolidones via Phosphine

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