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1 Electronic Supplementary Material (ESI) for Organic & Biomolecular Chemistry. This journal is The Royal Society of Chemistry 2019 Supporting Information for En-route to 3-Spiroindolizines Containing Isoindole Ring Through Intramolecular Arylation of Spiro-N-Acyliminium Species: A new Family of Potent Farnesyltransferase Inhibitors Anthony Pesquet, a Hamid Marzag, a Michael Knorr, b Carsten Strohmann, c Ata Martin Lawson, a Alina Ghinet, d,e,f,* Joëlle Dubois, g Amaury Farce, f,h Adam, Daïch, a,,*1 and Mohamed Othman a,* a Normandie Univ, UNILEHAVRE, CNRS, URCOM, Le Havre, France. b Institut UTINAM UMR CNRS 6213, Université Bourgogne Franche-Comté, 16 Route de Gray, Besançon, France c Anorganische Chemie, Technische Universität Dortmund, Otto-Hahn-Strasse 6, Dortmund, Germany d Faculty of Chemistry, Al. I. Cuza University of Iasi, B-dul Carol I, Nr. 11, Corp A, , Iasi, Romania e Laboratoire de Pharmacochimie, HEI, Yncréa Hauts-de-France, UCLille, 13 rue de Toul, BP 41290, F Lille Cedex, France f Univ. Lille, Inserm, CHU Lille, U995-LIRIC-Lille Inflammation Research International Center, F Lille, France g Institut de Chimie des Substances Naturelles, UPR2301, CNRS, Centre de Recherche de Gif, Avenue de la Terrasse, F Gif-sur- Yvette Cedex, France h Faculté des Sciences Pharmaceutiques et Biologiques de Lille, 3 Rue du Pr Laguesse, B.P. 83, F Lille, France adam.daich@univ-lehavre.fr ; ORCID Adam Daïch: orcid.org/ Table of contents I. General remarks S2 II. General procedure for the preparation of spirosuccinimides (±)-10a-c S2 III. General procedure for the synthesis of α-acetoxy lactams (±)-6a-c(A,A ) and 6a-c(B,B ) S4 IV. General Procedure for the Peptide Coupling S7 V. General Procedure for the Preparation of Spiro-hydroxy lactams (±)-11a,b,e,f and (±)-22 S9 VI. Procedure for the preparation of compound (±)-24 S13 VII. Procedure for the preparation of compound (±)-23 S13 VIII. Procedure for the preparation of compound (±)-25 S14 IX. General procedure for -cationic cyclization of α-acetoxy lactams (±)-6 S15 X. General procedure for -cationic cyclization of α-hydroxy lactams (±)-11 S16 XI. Copies of 1 H and 13 C NMR spectra for all new compounds S19 XII. Crystallographic data of compound (±)-7bA S48 XIII. CheckCIFreportch060707/Product (±)-7bA S54 S Corresponding author. Tel.: (+0033) ; adam.daich@univ-lehavre.fr ; ORCID AD: orcid.org/ Complete address: Normandie Univ, UNILEHAVRE, URCOM EA 3221, INC3M CNRS-FR 3038, UFR des Sciences et Techniques, Université Le Havre Normandie, BP : 1123, 25 rue Philipe Lebon, F Le Havre Cedex, France -S1-

2 I. General remarks Solvents (CH 2 Cl 2, CH 3 CN) were distilled prior to use, taking precaution to exclude moisture by refluxing over CaH 2. All reactions were performed under argon inert atmosphere. All glass apparatus was oven dried and cooled under vacuum before use. Thin layer chromatography (TLC) was performed on pre-coated sheets of silica gel 60 with fluorescent indicator UV 254 (Merck). Detection was accomplished by irradiation with a UV lamp and by an ethanolic solution of p-anisaldehyde. Chromatographic separations were achieved on silica gel columns (Kieselgel 60, μm, Merck) typically using a cyclohexane/ethyl acetate eluent system. In all cases, distilled solvents were used as eluents for column chromatography. Melting points were determined on a Stuart Scientific SMP 10 analyzer and are uncorrected. The infrared spectra (IR) were recorded on a Perkin-Elmer FT-IR Paragon 1000 spectrometer. 1 H NMR and 13 C NMR spectra were recorded on a Bruker Avance TM 300 MHz spectrometer. Chemical shifts are reported in parts per million (δ). Mass spectra (GC-MS) were obtained on a ThermoFinnigan Automass III spectrometer coupled with a gas chromatograph Trace GC High resolution mass spectra (HRMS) were measured on a Agilent 6530 Q-Tof MS system. II. General procedure for the preparation of spirosuccinimides (±)-10a-c To a solution of N-alkylated isoindolin-1-one 5 (0.01 mol) in 100 ml of CH 3 CN anhydrous were added potassium carbonate (0.015 mol, 2.07 g) and bromoacetamide 9 (0.015 mol) under dry argon atmosphere. The mixture was then refluxed for 24 h. The solution was cooled at room temperature and filtered through a plug of celite. After removal of solvents under reduced pressure, the crude was analysed by 1 H NMR spectroscopy then purified by flash chromatography on silica gel column using a mixture of cyclohexane/acoet (4/1) as eluent. (±)-2-Benzyl-1'-phenethylspiro[isoindoline-1,3'-pyrrolidine]-2',3,5'-trione (10a) Spirosuccinimide (±)-10a: This product was isolated as a white solid in 75% yield after crystallization from anhydrous ethanol; R f (cyclohexane/acoet: 3/2) = 0.5; Mp = C; IR (ATR) , cm -1 ; 1 H NMR (300 MHz, CDCl 3 ): 2.78 (d, J = 18.0 Hz, 1H, CH 2 ), 2.88 (d, J = 18.0 Hz, 1H,CH 2 ), (m, 2H, CH 2 ), (m, 2H, CH 2 ), 4.20 (d, J = 16.0 Hz, 1H, CH 2 ), 5.05 (d, J = 16 Hz, 1H, CH 2 ), 6.78 (d, J = 7.0 Hz, 1H, H aro ), (m, 10H, H aro ), (m, 2H, H aro ), (m, 1H, H aro ) ppm. 13 C NMR (75 MHz, CDCl 3 ): 32.8 (CH 2 ), 37.3 (CH 2 ), 40.0 (CH 2 ), 44.2 (CH 2 ), 68.3 (C q ), (CH aro ), (CH aro ), (CH aro ), (3 x CH aro ), (2 x CH aro ), (4 x CH aro ), (CH aro ), 130.8(C q aro), (CH aro ), (C q aro), -S2-

3 136.9 (C q aro), (C q aro), (C=O), (C=O), (C=O) ppm. HRMS (+ESI) calculated for C 26 H 23 N 2 O 3 [M+H] + : , found: (±)-2-Benzyl-1'-(3,4-dimethoxyphenethyl)spiro[isoindoline-1,3'-pyrrolidine]-2',3,5'-trione (10b) Spirosuccinimide (±)-10b: This product was isolated as a white solid in 66% yield after crystallization from anhydrous ethanol; R f (cyclohexane/acoet: 2/3) = 0.42; Mp = C; IR (ATR) , cm -1 ; 1 H NMR (200 MHz, CDCl 3 ): 2.72 (d, J = 18 Hz, 1H, CH 2 ), 2.85 (d, J = 18 Hz, 1H, CH 2 ), (m, 2H, CH 2 ), 3.77 (s, 3H, OCH 3 ), (m, 2H, CH 2 ), 3.86 (s, 3H, OCH 3 ), 4.15 (d, J = 16 Hz, 1H, CH 2 ), 5.06 (d, J = 16 Hz, 1H, CH 2 ), (m, 4H, H aro ), (m, 5H, H aro ), (m, 2H, H aro ), 7.89 (d, J = 6.8 Hz, 1H, H aro ) ppm. 13 C NMR (50 MHz, CDCl 3 ): 32.2 (CH 2 ), 37.3 (CH 2 ), 39.8 (CH 2 ), 44.3 (CH 2 ), 55.9 (OCH 3 ), 56.0 (OCH 3 ), 68.4 (C q ), (CH aro ), (CH aro ), (CH aro ), (CH aro ), (CH aro ), (2 x CH aro ), (CH aro ), (2 x CH aro ), (C q aro), (CH aro ), (C q aro), (CH aro ), (C q aro), (C q aro), (C q aro), (C q aro), (C=O), (C=O), (C=O) ppm. HRMS (+ESI) calculated for C 28 H 27 N 2 O 5 [M+H] + : , found (±)-2-((1,5-Dimethyl-1H-pyrrol-2-yl)methyl)-1'-phenethylspiro[isoindoline-1,3'-pyrrolidine]- 2',3,5'-trione (10c) Spirosuccinimide (±)-10c: This compound was isolated as a white solid in 34% yield after crystallization from anhydrous ethanol; R f (cyclohexane/acoet: 2/3) = 0.42; Mp = C ;IR (ATR) cm -1 ; 1 H NMR (300 MHz, CDCl 3 ): 2.19 (s, 3H, CH 3 ), 2.83 (d, J = 18.0 Hz, 1H, CH 2 ), (m, 2H, CH 2 ), 3.06 (d, J = 18.0 Hz, 1H, CH 2 ), 3.39 (s, 3H, CH 3 ), (m, 1H, CH 2 ), (m, 1H, CH 2 ), 4.41 (d, J = 18.0 Hz, 1H, CH 2 ), 5.18 (d, J = 18.0 Hz, 1H, CH 2 ), 5.72 (d, J = 3.0 Hz, 1H, H aro ), 5.84 (d, J = 3.0 Hz, 1H, H aro ), 6.54 (d, J = 6.0 Hz, 1H, H aro ), (m, 2H, H aro ), (m, 3H, H aro ), (m, 1H, H aro ), (m, 1H, H aro ), 7.87 (d, J = 9.0 Hz, 1H, H aro ) ppm. 13 C NMR (75 MHz, CDCl 3 ): 12.4 (CH 3 ), 30.3 (CH 3 ), 32.8 (CH 2 ), 35.8 (CH 2 ), 36.1 (CH 2 ), 39.9 (CH 2 ), 66.8 (C q ), (CH aro ), (CH aro ), (CH aro ), (C q aro), (CH aro ), (CH aro ), (2 x CH aro ), (2 x CH aro ), (CH aro ), (C q aro), (C q aro), (CH aro ), (C q aro), 144.7(C q aro), (C=O), (2 x C=O) ppm. HRMS (+ESI) calculated for C 28 H 26 N 3 NaO 3 [M+Na] + : , found S3-

4 III. General procedure for the synthesis of α-acetoxy lactams (±)-6a-c (A,A ) and (±)-6a-c (B,B ) To a solution of spirosuccinimide (±)-10a-c (2.5 mmol) in a mixture of THF/EtOH (1:1) was added sodium borohydride (10 mmol, 4 equiv.) at 0 C then the mixture was left under stirring at room temperature for 4 h. The reaction mixture was then cooled to 0 C and quenched by addition of 1 ml of water then acidified to ph 3 by 2M HCl solution. The mixture was extracted twice by 30 ml of dichloromethane and the organic layer was dried over MgSO 4 then evaporated to dryness. The oily residue was purified by flash chromatography on a silica gel column using a mixture of cyclohexane/acoet (4/1) as eluent. In a second step, acetic anhydride (2 equiv.) was added dropwise to a solution of the above hydroxy lactams (±)-11a-c (1 equiv.), NEt 3 (2 equiv.), and DMAP (0.1 equiv.) in CH 2 Cl 2 (10 ml per 1 mmol of hydroxy lactam 11). The mixture was stirred at room temperature overnight and quenched by addition of a saturated aqueous solution of NaHCO 3. The aqueous layer was extracted with CH 2 Cl 2 (20 ml), and organic layers were combined, dried over MgSO 4, and evaporated. The acetate derivatives (±)-6 were then obtained after purification of the residue by flash chromatography on a silica gel column. (±)-2-Benzyl-3,5'-dioxo-1'-phenethylspiro[isoindoline-1,3'-pyrrolidin]-2'-yl acetate (±)-6a(A,A ) Spirosuccinimide (±)-10a gave a mixture of two regioisomers (±)-6a(A,A ) and (±)-6a(B,B ) and each regioisomer was obtained as two diastereoisomers in an overall yield of 80%. The product (±)-6a(A) was isolated as a white solid in 23% yield. R f (cyclohexane/acoet: 2/3) = 0.56; Mp = C; IR (ATR) , cm -1 ; 1 H NMR (300 MHz, CDCl 3 ): 1.81 (s, 3H, CH 3 ), 2.38 (d, J = 18 Hz, 1H, CH 2 ), (m, 2H, CH 2 ), 3.06 (d, J = 17 Hz, 1H, CH 2 ), (m, 1H, CH 2 ), (m, 1H, CH 2 ), 4.74 (d, J = 16 Hz, 1H, CH 2 ), 5.18 (d, J = 16 Hz, 1H, CH 2 ), 6.18 (s, 1H, CH), 6.92 (d, J = 8 Hz, 1H, H aro ), (m, 10H, H aro ), (m, 2H, H aro ), (m, 1H, H aro ) ppm. 13 C NMR (75 MHz, CDCl 3 ): 20.6 (CH 3 ), 33.4 (CH 2 ), 36.8 (CH 2 ), 41.8 (CH 2 ), 45.3 (CH 2 ), 65.7 (C q ), 86.5 (CH), (CH aro ), (CH aro ), (2 x CH aro ), (CH aro ), (CH aro ), (2 x CH aro ), (2 x CH aro ), (2 x CH aro ), (CH aro ), (C q aro), (CH aro ), (C q aro), (C q aro), (C q aro), (C=O), (C=O), (C=O) ppm. HRMS (+ESI) calculated for C 28 H 26 N 2 NaO 4 [M+Na] + : , found α-acetoxylactam (±)-6a(A ) was isolated as white solid in 7% yield. R f (cyclohexane/acoet: 2/3) = 0.58; Mp = C; IR (ATR) , cm -1 ; 1 H NMR (300 MHz, CDCl 3 ): 1.89 (s, 3H, CH 3 ), 2.52 (d, J = 18.0 Hz, 1H, CH 2 ), (m, 1H, CH 2 ), (m, 1H, CH 2 ), 3.06 (d, J = 18.0 Hz, 1H, CH 2 ), (m, 2H, CH 2 ), 4.52 (d, J = 15 Hz, 1H, CH 2 ), 4.60(d, J = 15 Hz, 1H, CH 2 ), 6.06 (s, 1H, CH), (m, 9H, H aro ), (m, 1H, H aro ), (m, 2H, H aro ), (m, 2H, H aro ) ppm. 13 C NMR (75 MHz, CDCl 3 ): 20.8 (CH 3 ), 33.5 (CH 2 ), 39.4 (CH 2 ), -S4-

5 42.7 (CH 2 ), 43.3 (CH 2 ), 67.6 (C q ), 87.7 (CH), (CH aro ), (CH aro ), ( CH aro ), (2 x CH aro ), (CH aro ), (2 x CH aro ), (2 x CH aro ), (2 x CH aro ), (CH aro ), (C q aro), (CH aro ), (C q aro), (C q aro), (C q aro), (C=O), (C=O), (C=O) ppm. HRMS (+ESI) calculated for C 28 H 26 N 2 NaO 4 [M+Na] + : , found α-acetoxylactams (±)-6a(B,B ) were obtained as inseparable mixture together with products (±)- 6a(A,A ), thus their NMR characteristics were not extracted from the spectrum because of its complexity. (±)-2-Benzyl-1'-(3,4-dimethoxyphenethyl)-3,5'-dioxospiro[isoindoline-1,3'-pyrrolidin]-2'-yl acetate (±)-6b(A,A ) and (±)-6b(B,B ) Spirosuccinimide (±)-10b gave a mixture of two regioisomers (±)-6b(A,A ) and (±)-6b(B,B ) and each regioisomer was obtained as two diastereoisomers in an overall yield of 98%. The 1 H NMR characteristics of these products were extracted from the spectrum of the mixture. Major diastereoisomer (±)-6b(A): 1 H NMR (300 MHz, CDCl 3 ): 1.75 (s, 3H, CH 3 ), 2.29 (d, J = 17.0 Hz, 1H, CH 2 ), 2.98 (d, J = 17.0 Hz, 1H, CH 2 ), 3.76 (s, 3H, OCH 3 ), (m, 2H, CH 2 ), 3.81 (s, 3H, OCH 3 ), 4.67 (d, J = 16.0 Hz, 1H, CH 2 ), 5.14 (d, J = 16.0 Hz, 1H, CH 2 ), 6.21 (s, 1H, CH), (m, 3H, H aro ), (m, 8H, H aro ), (m, 1H, H aro ) ppm. Minor diastereoisomer (±)-6b(A ): 1 H NMR (300 MHz, CDCl 3 ): 1.81 (s, 3H, CH 3 ), 2.44 (d, J = 18.0 Hz, 1H, CH 2 ), (m, 1H, CH 2 ), 2.97 (d, J = 18.0 Hz, 1H, CH 2 ), 3.22 (t, J = 8.0 Hz, 2H, CH 2 ), 3.76 (s, 3H, OCH 3 ), 3.80 (s, 3H, OCH 3 ), (m, 1H, CH 2 ), 4.49 (s, 2H, CH 2 ), 5.99 (s, 1H, CH), (m, 3H, H aro ), (m, 8H, H aro ), (m, 1H, H aro ) ppm. (±)-2-Benzyl-1'-(3,4-dimethoxyphenethyl)-2',3-dioxospiro[isoindoline-1,3'-pyrrolidin]-5'-yl acetate (±)-6b(B,B ) The 1 H NMR characteristics of these products were extracted from the spectrum of the mixture. Major diastereoisomer (±)-6b(B): 1 H NMR (300 MHz, CDCl 3 ): 2.04 (d, J = 15.0 Hz, 1H, CH 2 ), 2.12 (s, 3H, CH 3 ), 2.16 (dd, J = 3.0, 15.0 Hz, 1H, CH 2 ), (m, 2H, CH 2 ), 3.50 (d, J = 16.2 Hz, 1H, CH 2 ), 3.77 (s, 3H, OCH 3 ), (m, 2H, CH 2 ), 3.80 (s, 3H, OCH 3 ), 5.11 (d, J = 16.2 Hz, -S5-

6 1H, CH 2 ), 6.13 (s, 1H, CH), (m, 3H, H aro ), (m, 8H, H aro ), (m, 1H, H aro ) ppm. Minor diastereoisomer (±)-6b(B ): 1 H NMR (300 MHz, CDCl 3 ): 2.02 (s, 3H, CH 3 ), (m, 2H, CH 2 ), (m, 2H, CH 2 ), 3.63 (s, 3H, OCH 3 ), 3.82 (s, 3H, OCH 3 ), (m, 2H, CH 2 ), 4.22 (d, J = 16.1 Hz, 1H, CH 2 ), 5.09 (d, J = 16.6 Hz, 1H, CH 2 ), 6.22 (dd, J = 2.4, 7.0 Hz, 1H, CH), 6.29 (d, 1H, J = 7.43 Hz, 1H, H aro ), (m, 2H, H aro ), (m, 8H, H aro ), (m, 1H, H aro ) ppm. 13 C NMR (75 MHz, CDCl 3 ) of (±)-6b(A,A ) and (±)-6b(B,B ). The 13 C NMR characteristics of these products were given from the spectrum of the mixture: 20.5 (CH 3 ), 20.7 (CH 3 ), 21.0 (CH 3 ), 21.3 (CH 3 ), 32.2 (CH 2 ), 32.7 (2 x CH 2 ), 33.0 (CH 2 ), 34.7 (CH 2 ), 35.3 (CH 2 ), 36.7 (CH 2 ), 39.4 (CH 2 ), 41.1 (CH 2 ), 41.4 (CH 2 ), 42.3 (CH 2 ), 42.6 (CH 2 ), 43.2 (CH 2 ), 44.0 (CH 2 ), 44.1 (CH 2 ), 45.2 (CH 2 ), 55.8 (2 x OCH 3 ), 55.9 (2 x OCH 3 ), 56.0 (2 x OCH 3 ), 56.1 (2 x OCH 3 ), 65.5 (C q ), 67.5 (C q ), 69.5 (C q ), 70.0 (C q ), 79.9 (CH), 80.0 (CH), 86.3 (CH), 87.6 (CH), (2 x CH aro ), (3 x CH aro ), (CH aro ), (CH aro ), (CH aro ), (CH aro ), (CH aro ), (CH aro ), (CH aro ), (CH aro ), (CH aro ), (CH aro ), (CH aro ), (CH aro ), (CH aro ), (CH aro ), (2 x CH aro ), (3 x CH aro ), (3 x CH aro ), (CH aro ), (CH aro ), (CH aro ), (CH aro ), (2 x CH aro ), (2 x CH aro ), (3 x CH aro ), (CH aro ), (CH aro ), (CH aro ), (CH aro ), (C q aro), (C q aro), (C q aro), (C q aro), (C q aro), (C q aro), (C q aro), (CH aro ), (CH aro ), (CH aro ), (2 x C q aro), (C q aro), (C q aro), (C q aro), (C q aro), (C q aro), (2 x C q aro), (C q aro), (C q aro), (C q aro), (C q aro), (C q aro), (C q aro), (C q aro), (C q aro), (2 x C=O), (C=O), (C=O), (C=O), (C=O), (2 x C=O), (C=O), (2 x C=O), (C=O) ppm; HRMS (+ESI) calculated for C 30 H 30 N 2 NaO 6 [M+Na] + : , found (±)-2-((1,5-Dimethyl-1H-pyrrol-2-yl)methyl)-2',3-dioxo-1'-phenethylspiro[isoindoline-1,3'- pyrrolidin]-5'-yl acetate (±)-6c(B,B ) This product was obtained as a mixture of inseparable two diastereoisomers, R f (cyclohexane/acoet: 2/3) = 0.48, IR (ATR): cm -1. The NMR characteristics of these products were extracted from the spectrum of the mixture. Major diastereoisomer (±)-6c(B): 1 H NMR (300 MHz, CDCl 3 ): (m, 1H, CH 2 ), 2.15 (s, 3H, CH 3 ), 2.20 (s, 3H, CH 3 ), 2.76 (dd, J = 7.0, 15.0 Hz, 1H, CH 2 ), (m, 2H, CH 2 ), (m, 1H, CH 2 ), 3.45 (s, 3H, CH 3 ), (m, 1H, CH 2 ), 4.75 (d, J = 16.0 Hz, 1H, CH 2 ), 4.83 (d, J = 16.0 Hz, 1H, CH 2 ), (m, 1H, H aro ), (m, 1H, H aro ), 6.25 (d, J = 6.6 Hz, 1H, CH), (m, 5H, H aro ), (m, 3H, H aro ), (m, 1H, H aro ) ppm. 13 C NMR (75 MHz, CDCl 3 ): 12.4 (CH 3 ), 21.3 (CH 3 ), 30.4 (CH 3 ), 33.7 (CH 2 ), 33.8 (CH 2 ), 36.1 (CH 2 ), 43.9 (CH 2 ), 68.5 (C q ), 81.2 (CH), (CH aro ), (CH aro ), (CH aro ), (CH aro ), (C q aro), S6-

7 (CH aro ), (2 x CH aro ), (2 x CH aro ), (CH aro ), (C q aro), (C q aro), (CH aro ), (C q aro), (C q aro), (C=O), (2 x C=O) ppm. Minor diastereoisomer (±)-6c(B ): 1 H NMR (300 MHz, CDCl 3 ): 2.19 (s, 3H, CH 3 ), 2.24 (s, 3H, CH 3 ), 2.35 (dd, J = 3.6, 15.0 Hz, 1H, CH 2 ), 2.65 (dd, J = 7.1, 15.0 Hz, 1H, CH 2 ), (m, 2H, CH 2 ), (m, 1H, CH 2 ), 3.46 (s, 3H, CH 3 ), (m, 1H, CH 2 ), 4.71 (d, J = 16.0 Hz, 1H, CH 2 ), 4.91 (d, J = 16.0 Hz, 1H, CH 2 ), (m, 1H, H aro ), (m, 1H, H aro ), 6.32 (dd, J = 3.6, 7.1 Hz, 1H, CH), (m, 1H, H aro ), (m, 5H, H aro ), (m, 2H, H aro ), (m, 1H, H aro ) ppm. 13 C NMR (75 MHz, CDCl 3 ): 12.5 (CH 3 ), 21.1 (CH 3 ), 30.5 (CH 3 ), 32.9 (CH 2 ), 34.6 (CH 2 ), 36.0 (CH 2 ), 41.2 (CH 2 ), 68.8 (C q ), 80.0 (CH), (CH aro ), (CH aro ), (CH aro ), (CH aro ), (C q aro), (CH aro ), (2 x CH aro ), (2 x CH aro ), (CH aro ), (C q aro), (C q aro), (CH aro ), (C q aro), (C q aro), (C=O), (C=O), (C=O) ppm. HRMS (+ESI) calculated for C 28 H 30 N 3 O 4 [M+H] + : , found (±)-2-(2-((1,5-Dimethyl-1H-pyrrol-2-yl)methyl)-1-(hydroxymethyl)-3-oxoisoindolin-1-yl)-Nphenethylacetamide (±)-12c Compound (±)-12c: This product was isolated as a white solid in 34% yield after crystallization from anhydrous ethanol; R f (cyclohexane/acoet: 2/3) = 0.22; Mp = C ; IR (ATR): , cm -1 ; 1 H NMR (300 MHz, CDCl 3 ): 2.18 (s, 3H, CH 3 ), 2.48 (d, J = 14.0 Hz, 1H, CH 2 ), (m, 2H, CH 2 ), 2.88 (d, J = 14.0 Hz, 1H, CH 2 ), (m, 1H, CH 2 ), (m, 1H, CH 2 ), 3.49 (s, 3H, CH 3 ), 3.80 (d, J = 12.0 Hz, 1H, CH 2 ), 3.85 (d, J = 12.0 Hz, 1H, CH 2 ), 4.80 (d, J = 16.0 Hz, 1H, CH 2 ), 4.91 (d, J = 16.0 Hz, 1H, CH 2 ), (m, 1H, OH), 5.80 (d, J = 3.0 Hz, 1H, H aro ), 6.08 (d, J = 3.0 Hz, 1H, H aro ), (m, 2H, H aro ), (m, 6H, H aro ), 7.82 (d, J = 7.0 Hz, 1H, H aro ) ppm. 13 C NMR (75 MHz, CDCl 3 ): 12.6 (CH 3 ), 30.7 (CH 3 ), 35.7 (CH 2 ), 35.9 (CH 2 ), (2 x CH 2 ), 66.7 (CH 2 ), 66.5 (C q ), (CH aro ), (CH aro ), (CH aro ), (CH aro ), (CH aro ), (C q aro), (2 x CH aro ), (2 x CH aro ), (CH aro ), (C q aro), (C q aro), (CH aro ), (C q aro), (C q aro), (C=O), (C=O) ppm. HRMS (+ESI) calculated for C 26 H 29 N 3 NaO 3 [M+Na] + : , found IV. General Procedure for the Peptide Coupling To a solution of carboxylic acid (±)-17 (5 mmol, 1.53 g) along with the appropriate amine (5 mmol), HOBt (5 mmol, 0.67 g), and NEt 3 (5 mmol, 0.70 ml) in dry CHCl 3 (50 ml) was added a solution of EDCI.HCl (5 mmol, 0.96 g) in CHCl 3 (50 ml). The reaction mixture was stirred at room temperature under argon atmosphere overnight. After the reaction was completed (TLC), the solution was washed with 1N NaHCO 3 solution, 10% citric acid solution then saturated NaCl solution. The organic layer was dried and concentrated under reduced pressure. The obtained solid crude was recrystallized in anhydrous EtOH to afford the product as a white solid in 87 to 99 % yield. -S7-

8 (±)-1-Allyl-N-benzyl-3-oxo-N-phenethylisoindoline-1-carboxamide (±)-19a Starting from the phenyl ethylamine, this product was isolated as white solid in 87% yield; R f (cyclohexane/acoet: 2/3) = 0.77; Mp = C; IR (ATR): , cm -1 ; 1 H NMR (200 MHz, CDCl 3 ): 2.36 (t, J = 7.0 Hz, 2H, CH 2 ), (m, 1H, CH 2 ), (m, 1H, CH 2 ), (m, 2H, CH 2 ), 4.41 (d, J = 15 Hz, 1H, CH 2 ), (m, 4H, CH 2 ), 5.58 ( s broad, 1H, NH), (m, 2H, H aro ), (m, 11H, H aro ), 7.74 (d, J = 7.0 Hz, 1H, H aro ) ppm. 13 C NMR (50 MHz, CDCl 3 ): 34.8 (CH 2 ), 36.7 (CH 2 ), 40.7 (CH 2 ), 44.6 (CH 2 ), 72.5 (C q ), (CH 2 =), (CH = ), (CH aro ), (CH aro ), (CH aro ), (2 x CH aro ), (2 x CH aro ), (2 x CH aro ), (3 x CH aro ), (CH aro ), (C q aro), (CH aro ), (C q aro), (C q aro), (C q aro), (C=O), (C=O) ppm. HRMS (+ESI) calculated for C 27 H 27 N 2 O 2 [M+H] + : , found (±)-1-Allyl-N-benzyl-N-(3,4-dimethoxyphenethyl)-3-oxoisoindoline-1-carboxamide (±)-19b This product was isolated as white solid in 99% yield; R f (cyclohexane/acoet: 3/2) = 0.37; Mp = C; IR (ATR): , cm -1 ; 1 H NMR (200 MHz, CDCl 3 ): 2.19 (t, J = 7.0 Hz, 2H, CH 2 ), (m, 1H, CH 2 ), (m, 1H, CH 2 ), (m, 1H, CH 2 ), (m, 1H, CH 2 ), 3.80 (s, 3H, OCH 3 ), 3.85 (s, 3H, OCH 3 ), 4.33 (d, J = 15 Hz, 1H, CH 2 ), (m, 3H, CH 2 ), 4.94 (d, J = 15.0 Hz, 1H, CH 2 ), 5.20 (s broad, 1H, NH), 6.27 (dd, J = 2.0, 7.0 Hz, 1H, H aro ), 6.40 (d, J = 2.0 Hz, 1H, H aro ), 6.63 (d, J = 7.0 Hz, 1H, H aro ), (m, 3H, H aro ), (m, 5H, H aro ), 7.87 (dd, J = 2.0, 7.0 Hz, 1H, H aro ) ppm. 13 C NMR (50 MHz, CDCl 3 ): 34.3 (CH 2 ), 36.7 (CH 2 ), 40.6 (CH 2 ), 44.5 (CH 2 ), 55.7 (OCH 3 ), 55.9 (OCH 3 ), 72.3 (C q ), (CH aro ), (CH aro ), (CH 2 =), (CH=),122.0 (CH aro ), (CH aro ), (CH aro ), (2 x CH aro ), (3 x CH aro ), (CH aro ), (2 x C q aro), (CH aro ), (C q aro), (C q aro), (C q aro), (C q aro), (C=O), (C=O) ppm. HRMS (+ESI) calculated for C 29 H 31 N 2 O 4 [M+H] + : , found (±)-1-Allyl-N,N-dibenzyl-3-oxoisoindoline-1-carboxamide (±)-19e -S8-

9 Starting from the benzylamine, this product was isolated as white solid in 97% yield; R f (cyclohexane/acoet: 3/2) = 0.57; Mp = C; IR (KBr): , cm -1 ; 1 H NMR (200 MHz, CDCl 3 ): (m, 1H, CH 2 ), (m, 1H, CH 2 ), 3.62 (dd, J = 5.0, 15.0 Hz, 1H, CH 2 ), 4.20 (dd, J = 7.0, 15.0 Hz, 1H, CH 2 ), 4.43 (d, J = 15.0 Hz, 1H, CH 2 ), (m, 3H, CH 2 ), 4.94 (d, J = 15.0 Hz, 1H, CH 2 ), 5.83 ( s broad, 1H, NH), (m, 2H, H aro ), (m, 3H, H aro ), (m, 3H, H aro ), (m, 5H, H aro ), 7.73 (d, J = 7.0 Hz, 1H, H aro ) ppm. 13 C NMR (50 MHz, CDCl 3 ): 36.8 (CH 2 ), 43.6 (CH 2 ), 44.9 (CH 2 ), 72.7 (C q ), (CH 2 =), (CH=), (CH aro ), (2 x CH aro ), (CH aro ), (2 x CH aro ), (2 x CH aro ), (2 x CH aro ), (2 x CH aro ), (C q aro), (2 x CH aro ), (C q aro), (C q aro), (C q aro), (C=O), (C=O) ppm. HRMS (+ESI) calculated for C 26 H 25 N 2 O 2 [M+H] + : , found (±)-1-Allyl-N-benzyl-3-oxo-N-(prop-2-yn-1-yl)isoindoline-1-carboxamide (±)-19f Starting from propargylamine, this product was isolated as white solid in 97% yield ; R f (cyclohexane/acoet: 3/2) = 0.57; Mp = C; IR (ATR): cm -1 ; 1 H NMR (200 MHz, CDCl 3 ): 2.02 (t, J = 2.0 Hz, 1H, CH 2 ), (m, 1H, CH 2 ), (m, 2H, CH 2 ), (m, 1H, CH 2 ), 4.41 (d, J = 15.0 Hz, 1H, CH 2 ), (m, 3H, CH=CH 2 ), 5.00 (d, J = 15.0 Hz, 1H, CH 2 ), 5.58 (s broad, 1H, NH), (m, 3H, H aro ), (m, 5H, H aro ), 7.81 (d, J= 7.0 Hz, 1H, H aro ) ppm. 13 C NMR (50 MHz, CDCl 3 ): 29.4 (CH 2 ), 36.7 (CH 2 ), 44.9 (CH 2 ), 71.5 (C q ), 72.5 (C q ), 78.8 (CH), (CH 2 =), (CH=), (CH aro ), (CH aro ), (2 x CH aro ), (CH aro ), (2 x CH aro ), (CH aro ), (C q aro), (CH aro ), (C q aro), (C q aro), (C=O), (C=O) ppm. HRMS (+ESI) calculated for C 22 H 21 N 2 O 2 [M+H] + : , found Methyl 2-(2-benzyl-3-oxo-1-(prop-2-yn-1-yl)isoindoline-1-carboxamido)acetate (±)-20 This product was isolated from reaction between (±)-18 and glycine methyl ester hydrochloride as a white solid in 75% yield after crystallization from anhydrous ethanol; R f (cyclohexan/acoet: 3/2)= 0.5; Mp= C; IR (ATR) , cm -1 ; 1 H NMR (300 MHz, CDCl 3 ) 1.66 (t, J = 2.6 Hz, 1H, CH), 3.11 (dd, J = 2.6, 17.5 Hz, 1H, CH 2 ), 3.38 (dd, J = 2.6, 17.5 Hz, 1H, CH 2 ), 3.39 (d, J = 17.7 Hz, 1H, CH 2 ), 3.63 (s, 3H, CH 3 ), 3.71 (dd, J = 5.8, 17.7 Hz, 1H, CH 2 ), 4.60 (d, J = 15.2 Hz, 1H, CH 2 ), 5.04 (d, J = 15.2 Hz, 1H, CH 2 ), 6.18 (t, J = 5.8 Hz, 1H, NH), (m, 3H, H aro ), (m, 5H, H aro ), 7.82 (d, J = 7.4 Hz, 1H, H aro ) ppm. 13 C NMR (75 MHz, CDCl 3 ) 24.4 (CH 3 ), 41.1 (CH 2 ), 44.5 (CH 2 ), 52.2 (CH 2 ), 70.8 (C q ), 72.1 (C q ), 77.2 (CH), (CH aro ), (CH aro ), (CH aro ), (2 x CH aro ), (2 x CH aro ), (CH aro ), (C q aro), S9-

10 (CH aro ), (C q aro), (C q aro), (C=O), (C=O), (C=O) ppm. HRMS (+ESI) calculated for C 22 H 20 N 2 O 4 [M+H] + : , found: V. General Procedure for the Preparation of Spiro-hydroxy lactams (±)-11a,b,e,f(B,B ) and (±)-22 OsO 4 (4%, w/w solution in water, 0.76 ml, 0.12 mmol) was added to a solution of 19a,b,e,f or 17g 2 (2 mmol) in 40 ml of THF/H 2 O (3/1), under argon atmosphere. The reaction mixture was stirred at room temperature for 20 min then NaIO 4 (6 mmol, 1.28 g) was slowly added. After 2 to 3 h of stirring, water (30 ml) was added and the mixture was extracted with CH 2 Cl 2 (2 x 40 ml). The combined organic layers were washed with brine, dried over MgSO 4 then evaporated to dryness. The oil residue was purified by flash chromatography on silica gel column using the mixture cyclohexane/acoet (4/1) as the eluent. N-Benzyl-5'-hydroxy-N'-phenethylspiro[isoindoline-1,3'-pyrrolidine]-2',3-dione (±)-11a(B,B ) This products was obtained as a mixture of inseparable two diastereoisomers in 55:45 ratio, and were isolated as white solid in 54% global yield; R f (cyclohexane/acoet: 3/2) = Major diastereoisomer (±)-11a(B): The NMR characteristics of this product were extracted from the spectrum of the mixture; 1 H NMR (200 MHz, DMSO-d 6 ): (m, 1H, CH 2 ), (m, 1H, CH 2 ), (m, 2H, CH 2 ), (m, 1H, CH 2 ), (m, 1H, CH 2 ), 3.75 (d, J = 16 Hz, 1H, CH 2 ), 4.81(d, J = 16.0 Hz, 1H, CH 2 ), 5.25 (t, J = 5.0 Hz, 1H, CH), 6.93 (d, J = 5.0 Hz,1H, OH), (m, 10H, H aro ), (m, 3H, H aro ), 7.83 (d, J = 8Hz, 1H, H aro ) ppm. 13 C NMR (50 MHz, CDCl 3 ): 32.6 (CH 2 ), 36.2 (CH 2 ), 41.2 (CH 2 ), 43.0 (CH 2 ), 70.7 (C q ), 77.9 (CH), (CH aro ), (CH aro ), (2 x CH aro ), (2 x CH aro ), (4 x CH aro ), (3 x CH aro ), (C q aro), (CH aro ), (C q aro), (C q aro), (C q aro), (C=O), (C=O). Minor diastereoisomer (±)-11a(B ): The NMR characteristics of this product were extracted from the spectrum of the mixture; 1 H NMR (200 MHz, DMSO-d 6 ): (m, 1H, CH 2 ), 2.68 (dd, J = 6.5, 14.3 Hz, 1H, CH 2 ), (m, 2H, CH 2 ), (m, 1H, CH 2 ), (m, 1H, CH 2 ), 4.24 (d, J = 16.0 Hz, 1H, CH 2 ), 4.89 (d, J = 16.0 Hz, 1H, CH 2 ), (m, 1H, CH), 6.76 (d, J = 6.5 Hz, 1H, OH), (m, 1H, H aro ), (m, 10H, H aro ), (m, 3H, H aro ) ppm. 13 C NMR (50 MHz, DMSO-d 6 ): 32.5 (CH 2 ), 37.3 (CH 2 ), 40.5 (CH 2 ), 43.2 (CH 2 ), 70.5 (C q ), 78.0 (CH), (CH aro ), (2 x CH aro ), (2 x CH aro ), (CH aro ), (3 x CH aro ), (3 x CH aro ), (CH aro ), (C q aro), (CH aro ), (C q aro), (C q aro), (C q aro), (C=O), (C=O) ppm. HRMS (+ESI) calculated for C 26 H 25 N 2 O 3 [M+H] + : , found Rammah, M. M.; Othman, M.; Ciamala, K.; Knorr, M.; Strohmann, C.; Rammah, M. B. Heterocycles 2009, 78, S10-

11 N-Benzyl-N'-(3,4-dimethoxyphenethyl)-5'-hydroxyspiro[isoindoline-1,3'-pyrrolidine]-2',3-dione (±)-11b(B) This product was obtained as a mixture of inseparable two diastereoisomers in 50:50 ratio and 57% yield. Major diastereoisomer (±)-11b(B): The NMR characteristics of this product were extracted from the spectrum of the mixture; R f (cyclohexane/acoet: 2/3) = 0.27; 1 H NMR (300 MHz, DMSO-d 6 ): (m, 2H, CH 2 ), 2.40 (dd, J = 6.5, 14.4 Hz, 1H, CH 2 ), (m, 2H, CH 2 ), (m, 1H, CH 2 ), 3.66 (d, J = 16.4 Hz, 1H, CH 2 ), 3.71 ( s, 3H, OCH 3 ), 3.73 ( s, 3H, OCH 3 ), 4.81 (d, J = 16.4 Hz, 1H, CH 2 ), 5.26 (t, J = 5.4Hz, 1H, CH), (m, 3H, H aro ), 6.94 (d, J = 4.6 Hz, 1H, OH), (m, 2H, H aro ), (m, 2H, H aro ), (m, 2H, H aro ), (m, 2H, H aro ), 7.84 (d, J= 7.6 Hz, 1H,H aro ) ppm. 13 C NMR (75 MHz, DMSO-d 6 ): 32.6 (CH 2 ), 36.7 (CH 2 ), 41.4 (CH 2 ), 43.5 (CH 2 ), 55.8 (OCH 3 ), 55.9 (OCH 3 ), 71.2 (C q ), 78.3 (CH), (CH aro ), (CH aro ), (CH aro ), (CH aro ), (3 x CH aro ), (CH aro ), (2 x CH aro ), (CH aro ), 131.1(CH aro ), (C q aro), (C q aro), (C q aro), (C q aro), (C q aro), (C q aro), (C=O), (C=O) ppm. Minor diastereoisomer (±)-11b(B ):The NMR characteristics of this product were extracted from the spectrum of the mixture; R f (cyclohexane/acoet: 2/3) = 0.27; 1 H NMR (300 MHz, DMSO-d 6 ): (m, 2H, CH 2 ), 2.67 (dd, J = 6.5, 14.3 Hz, 1H, CH 2 ), (m, 2H, CH 2 ), (m, 1H, CH 2 ), 3.64 (s, 3H, OCH 3 ), (m, 1H, CH 2 ), 3.74 (s, 3H, OCH 3 ), 4.22 (d, J = 16.3 Hz, 1H, CH 2 ), 4.91 (d, J = 16.3 Hz, 1H, CH 2 ), (m, 1H, CH), (m, 4H, 3H aro + OH), (m, 7H, H aro ), (m, 1H, H aro ), (m, 1H, H aro ) ppm. 13 C NMR (75 MHz, DMSO-d 6 ): 32.3 (CH 2 ), 37.7 (CH 2 ), 40.7 (CH 2 ), 43.7 (CH 2 ), 55.8 (OCH 3 ), 56.0 (OCH 3 ), 71.1 (C q ), 78.2 (CH), (CH aro ), (CH aro ), (CH aro ), (CH aro ), (2 x CH aro ), (3 x CH aro ), (2 x CH aro ), (CH aro ), (C q aro), (C q aro), (C q aro), (C q aro), (C q aro), (C q aro), (C=O), (C=O) ppm. HRMS (+ESI) calculated for C 28 H 29 N 2 O 5 [M+H] + : , found N,N -Dibenzyl-5'-hydroxy-spiro[isoindoline-1,3'-pyrrolidine]-2',3-dione (±)-11e(B,B ) -S11-

12 This product was isolated as a mixture of inseparable two diastereoisomers in 53:47 ratio and 74% yield. IR (ATR) cm -1. The NMR characteristics of these products were extracted from the spectra of the mixture; R f (cyclohexane/acoet: 2/3) = Major diastereoisomer (±)-11e(B): 1 H NMR (CDCl 3 ): 2.09 (d, J = 14.8 Hz, 1H, CH 2 ), 2.35 (dd, J = 14.8, 6.7 Hz, 1H, CH 2 ), 3.87 (d, J = 16.2 Hz, 1H, CH 2 ), (m, 1H, CH), 4.26 (d, J = 14.0 Hz, 1H, CH 2 ), 4.92 (d, J = 13.3 Hz, 1H, CH 2 ), 5.01 (d, J = 5.5 Hz, 1H, CH 2 ), 5.21 (m, 1H, OH), 7.08 (dd, J = 6.8, 3.0 Hz, 2H, H aro ), (m, 7H, H aro ), (m, 1H, H aro ), 7.84 (dd, J = 10.4, 7.3 Hz, 4H, H aro ). Minor diastereoisomer (±)-11e(B ) : 1 H NMR (CDCl 3 ): 2.20 (dd, J = 14.6, 4.3 Hz, 1H, CH 2 ), 2.58 (dd, J = 14.7, 6.6 Hz, 1H, CH 2 ), 4.26 (d, J = 14.0 Hz, 1H, CH 2 ), 4.37 (d, J = 16.0 Hz, 1H, CH 2 ), 4.71 (d, J = 4.7 Hz, 1H, OH), 4.93 (d, J = 7.5 Hz, 1H, CH 2 ), (m, 1H, CH), 5.30 (d, J = 16.3 Hz, 1H, CH 2 ), (m, 1H, H aro ), (m, 10H, H aro ), (m, 2H, H aro ), 7.84 (dd, J = 10.4, 7.3 Hz, 1H, H aro ) ppm. 13 C NMR (75 MHz, CDCl 3 ): δ 37.3 (CH 2 ), (CH 2 ), 44.0 (CH 2 ), 44.3 (CH 2 ), 44.3 (CH 2 ), 44.6 (CH 2 ), 70.7 (C q ), 71.1 (C q ), 78.2 (CH), 78.3 (CH), (CH aro ), (CH aro ), (CH aro ), (CH aro ), (2 x CH aro ), (2 x CH aro ), (CH aro ), (CH aro ), (CH aro ), (CH aro ), (2 x CH aro ), (3 x CH aro ), (3 x CH aro ), (2 x CH aro ), (CH aro ), (2 x CH aro ), (CH aro ), (C q aro), (C q aro), (CH aro ), (CH aro ), (C q aro), (C q aro), (C q aro), (C q aro), (C q aro), (C q aro), (C=O), (C=O), (2 x C=O) ppm. HRMS (+ESI) calculated for C 25 H 23 N 2 O 3 [M+H] + : , found 398, Benzyl-5'-hydroxy-N'-(prop-2-yn-1-yl)spiro[isoindoline-1,3'-pyrrolidine]-2',3-dione (±)- 11f(B,B ) This product was obtained as a mixture of partially separable two diastereoisomers in 55:45 ratio, and were isolated as white solid in 97% global yield; R f (cyclohexane/acoet: 3/2) = Major diastereoisomer (±)-11f(B): The NMR characteristics were extracted from the spectra of the mixture. 1 H NMR (300 MHz, CDCl 3 ): (m, 2H, CH 2 and C CH), 2.67 (dd, J = 6.6, 14.6 Hz, 1H, CH 2 ), (m, 1H, CH 2 ), (m, 1H, CH 2 ), 4.40 (d, J = 16.0 Hz, 1H, CH 2 ), 4.93 (d, J = 6.3 Hz, 1H, OH), 5.13 (d, J = 16.0 Hz, 1H, CH 2 ), (m, 1H, CH), (m, 6H, H aro ), (m, 2H, H aro ) (m, 1H, H aro ) ppm. 13 C NMR (75 MHz, CDCl 3 ): 29.8 (CH 2 ), 37.9 (CH 2 ), 44.2 (CH 2 ), 70.8 (C q ), 72.8 (CH), 77.0 (C q ), 78.1 (CH), (CH aro ), (CH aro ), (CH aro ), (2 x CH aro ), (2 x CH aro ), (CH aro ), (C q aro), (CH aro ), (C q aro), (C q aro), (C=O), (C=O) ppm. Minor diastereoisomer (±)-11f(B ): Pure fractions of this product were obtained by flash chromatography. Mp = C; IR (ATR): , cm -1 ; 1 H NMR (300 MHz, CDCl 3 ): 2.14 (d, J = 14.9 Hz, 1H, CH 2 ), 2.34 (t, J = 2.4 Hz, 1H, CCH), 2.47 (dd, J = 6.7, 14.8 Hz, 1H, CH 2 ), -S12-

13 3.99 (d, J = 16.0 Hz, 1H, CH 2 ), 3.94 (dd, J = 2.4, 17.5 Hz, 1H, CH 2 ), 4.40 (dd, J = 2.4, 17.5 Hz, 1H, CH 2 ), 4.67 (d, J = 4.4 Hz, 1H, OH), 5.24 (d, J = 16.0 Hz, 1H, CH 2 ), 5.42 (t, J = 5.2 Hz, 1H, CH), (m, 5H, H aro ), 7.45 (t, J = 7.4 Hz, 1H, H aro ), 7.52 (t, J = 7.4 Hz, 1H, H aro ), 7.74 (d, J = 7.7 Hz, 1H, H aro ), 7.84 (d, J = 7.2 Hz, 1H, H aro ) ppm. 13 C NMR (75 MHz, CDCl 3 ): 30.3 (CH 2 ), 37.0 (CH 2 ), 44.3 (CH 2 ), 71.1 (C q ), 72.3 (CH), 77.3 (C q ), 78.2 (CH), (CH aro ), (CH aro ), (2 x CH aro ), (CH aro ), (2 x CH aro ), (CH aro ), (C q aro), (CH aro ), (C q aro), (C q aro), (C=O), (C=O) ppm. HRMS (+ESI) Calculated for C 21 H 19 N 2 O found Methyl (±)-22 2-((1R)-2-benzyl-5'-hydroxy-2',3-dioxospiro[isoindoline-1,3'-pyrrolidin]-1'-yl)acetate This product was isolated as a white solid in 66% yield after crystallization from anhydrous ethanol; R f (cyclohexan/acoet: 2/3)= 0.32; Mp = C; IR (ATR) , cm -1 ; 1 H NMR (300 MHz, CDCl 3 ) 2.11 (d, J = 15.1 Hz, 1H, CH 2 ), 2.50 (dd, J = 6.7, 15.1 Hz, 1H, CH 2 ), 3.69 (s, 3H, CH 3 ), (m, 3H, CH 2 ), 4.81 (d, J = 3.8 Hz, 1H, CH), (m, 2H, CH 2 + OH), (m, 5H, H aro ), (m, 2H, H aro ), 7.68 (d, J = 7.4 Hz, 1H, H aro ), 7.77 (d, J = 7.4 Hz, 1H, H aro ) ppm. 13 C NMR (75 MHz, CDCl 3 ): 37.5 (CH 2 ), 42.5 (CH 2 ), 44.1 (CH 2 ), 52.7 (CH 3 ), 70.6 (C q ), (CH), (CH aro ), (CH aro ), (CH aro ), (2 x CH aro ), (2 x CH aro ), (CH aro ), (C q aro), (CH aro ), (C q aro), (C q aro), (C=O), (C=O), (C=O) ppm. HRMS (+ESI) calculated for C 21 H 20 N 2 O 5 [M+H] + : found: VI. Procedure for the preparation of compound (±)-24 To a solution of spiro-hydroxy lactam (±)-11e(B,B ) (mixture of two diastereoisomers) (0.75 mmol) in 7 ml of dry CH 2 Cl 2 was added Et 3 SiH (18.75 mmol, 3 ml) then trifluoroacetic acid (18.75 mmol, 1.4 ml). The reaction mixture was stirred at room temperature for 24 h. The solution was then diluted carefully with water (10 ml) and extracted twice with CH 2 Cl 2 (20 ml). The organic layer was neutralized with a cold 10% NaHCO 3 aqueous solution, dried over MgSO 4 and evaporated in vacuo to give an oil residue which was purified by flash column chromatography on silica gel column using cyclohexane-ethyl acetate (2/3) to give polyheterocyclic compound (±)-24. N',N-Dibenzylspiro[isoindoline-1,3'-pyrrolidine]-2',3-dione (±)-24 This compound was isolated as a white solid in 80% yield after crystallization from anhydrous ethanol. R f (cyclohexane/acoet: 2/3) = 0.56; Mp = C; IR (ATR): , cm -1 ; -S13-

14 1 H NMR (300 MHz, CDCl 3 ): (m, 2H, CH 2 ), (m, 1H, CH 2 ), (m, 1H, CH 2 ), 4.07 (d, J = 16.0 Hz, 1H, CH 2 ), 4.47 (d, J = 14.0 Hz, 1H, CH 2 ), 4.65 (d, J = 14.0 Hz, 1H, CH 2 ), 5.38 (d, J = 16.0 Hz, 1H, CH 2 ), (m, 1H, H aro ), (m, 7H, H aro ), (m, 3H, H aro ) (m, 2H, H aro ), (m, 1H, H aro ) ppm. 13 C NMR (75 MHz, CDCl 3 ): 28.3 (CH 2 ), 43.0 (CH 2 ), 44.3 (CH 2 ), 48.0 (CH 2 ), 71.0 (C q ), (CH aro ), (CH aro ), (CH aro ), (2 x CH aro ), (CH aro ), (3 x CH aro ), (2 x CH aro ), (2 x CH aro ), (C q aro), (CH aro ), (C q aro), (C q aro), (C q aro), (C=O), (C=O) ppm. HRMS (+ESI) calculated for C 25 H 23 N 2 O 2 [M+H] + : , found VII. Procedure for the preparation of compound (±)-23(B,B ) To a solution of spiro-hydroxy lactam (±)-11e(B,B ) (mixture of two diastereoisomers) (0.7 mmol) in 10 ml of dry toluene was added 1 equivalent of p-tsa. The reaction mixture was refluxed for 1h. After cooling at room temperature, the solution was concentrated in reduced pressure and diluted in 30 ml of dichloromethane. The organic layer was neutralized with a cold 10% NaHCO 3 aqueous solution, dried over MgSO 4 and evaporated under reduced pressure to give an oil residue which was purified by flash column chromatography on silica gel column using cyclohexane-ethyl acetate (7:3) to give polyheterocyclic compounds as following. N-Benzyl-N',9b'-dihydrospiro[isoindoline-1,2'-pyrrolo[2,1-a]isoindole]-3,3'(5'H)-dione (±)- 23(B,B ) Compound (±)-23(B,B ): This product was obtained as single diastereoisomer and was isolated as a yellow oil in 63% yield; R f (Cyclohexane/AcOEt : 3/2) = 0.54; IR (ATR): , cm -1 ; 1 H NMR (300 MHz, CDCl 3 ): δ 2.04 (d, J = 12.8 Hz, 1H, CH 2 ), 2.87 (dd, J = 12.7, 7.5 Hz, 1H, CH 2 ), 3.81 (d, J = 14.6 Hz, 1H, CH 2 ), 4.17 (d, J = 16.3 Hz, 1H, CH 2 ), 4.49 (d, J = 7.5 Hz, 1H, CH), 4.96 (d, J = 14.5 Hz, 1H, CH 2 ), 5.38 (d, J = 16.4 Hz, 1H, CH 2 ), 7.06 (d, J = 6.7 Hz, 1H, H aro ), (m, 8H, H aro ), 7.45 (t, J = 7.3 Hz, 2H, H aro ), 7.56 (t, J = 7.1 Hz, 1H, H aro ), 7.84 (d, J = 9 Hz, 1H, H aro ) ppm. 13 C NMR (75 MHz, CDCl 3 ): δ 41.0 (CH 2 ), 44.4 (CH 2 ), 45.6 (CH 2 ), 60.3 (CH), 71.4 (C q ), (CH aro ), (CH aro ), (CH aro ), (CH aro ), (2 x CH aro ), (2 x CH aro ), (CH aro ), (CH aro ), (CH aro ), (CH aro ), (CH aro ), (C q aro), (C q aro), (C q aro), (C q aro), (C q aro), (C=O), (C=O) ppm. HRMS (+ESI) Calculated for C 25 H 21 N 2 O 2 [M+H] + : , found: VIII. Procedure for the preparation of compound (±)-25 N-Benzyl-2',3-dioxo-N'-(prop-2-yn-1-yl)spiro[isoindoline-1,3'-pyrrolidin]-5'-yl acetate (±)-25 -S14-

15 This product was obtained as a mixture of inseparable two diastereoisomers in 63:37 ratio and 76% yield. IR (ATR): , cm -1. Major diastereoisomer (±)-25(B): The NMR characteristics of this product were extracted from the spectrum of the mixture: R f (cyclohexane/acoet : 2/3) = H NMR (300 MHz, CDCl 3 ): 2.10 (s, 3H, CH 3 ), (m, 1H+1H, CH 2 +C CH), 2.93 (dd, J = 7.0, 15.5 Hz, 1H, CH 2 ), 3.91 (dd, J = 2.5, 17.5 Hz, 1H, CH 2 ), 4.37 (d, J = 16.1 Hz, 1H, CH 2 ), 4.46 (dd, J = 2.5, 17.5 Hz, 1H, CH 2 ), 5.20 (d, J = 16.1 Hz, 1H, CH 2 ), 6.60 (dd, J = 2.5, 6.9 Hz, 1H, CH), (m, 6H, H aro ), (m, 2H, H aro ) (m, 1H, H aro ) ppm. 13 C NMR (75 MHz, CDCl 3 ): 20.9 (CH 3 ), 31.3 (CH 2 ), 35.7 (CH 2 ), 44.2 (CH 2 ), 69.4 (C q ), 73.2 (CH), 76.4 (C q ), 79.8 (CH), (CH aro ), (CH aro ), (CH aro ), (2 x CH aro ), (2 x CH aro ), (CH aro ), (C q aro), (CH aro ), (C q aro), (C q aro), (C=O),169.7 (C=O), (C=O) ppm. Minor diastereoisomer (±)-25(B ): The NMR characteristics of this product were extracted from the spectra of the mixture; 1 H NMR (300 MHz, CDCl 3 ): 2.23 (s, 3H, CH 3 ), 2.24 (d, 1H, J = 15.5 Hz, 1H, CH 2 ), (m, 1H, C CH), 2.71 (dd, J = 7.0, 15.5 Hz, 1H, CH 2 ), 3.99 (dd, J = 2.5, 17.5 Hz, 1H, CH 2 ), 4.09 (d, J = 16.0 Hz, 1H, CH 2 ), 4.44 (dd, J = 2.5, 17.5 Hz, 1H, CH 2 ), 5.30 (d, J = 16.0 Hz, 1H, CH 2 ), 6.44 (d, J = 6.7 Hz, 1H, CH), (m, 5H, H aro ), (m, 3H, H aro ), (m, 1H, H aro ) ppm. 13 C NMR (75 MHz, CDCl 3 ): 21.1 (CH 3 ), 31.6 (CH 2 ), 35.0 (CH 2 ), 44.3 (CH 2 ), 69.6 (C q ), 73.1 (CH), 76.6 (C q ), 79.8 (CH), (CH aro ), (CH aro ), (CH aro ), (2 x CH aro ), (2 x CH aro ), (CH aro ), (C q aro), (CH aro ), (C q aro), (C q aro), (C=O), (C=O), (C=O) ppm. HRMS (+ESI) calculated for C 23 H 21 N 2 O 4 [M+H] + : , found IX. General procedure for -cationic cyclization of α-acetoxy lactams (±)-6 To a solution of α-acetoxy lactam (±)-6 (pure form or mixture of two diastereoisomers or mixture of two regioisomers, 0.7 mmol) in 2 ml of acetonitrile was added 10 mol% of TMSOTf then the reaction mixture was stirred at room temperature for 24 h. The reaction mixture was then diluted carefully with water (10 ml) and extracted twice with dichloromethane (20 ml). The organic layer was dried over MgSO 4 and evaporated in vacuo to give an oil residue which was purified by flash column chromatography on silica gel column using the mixture of cyclohexane/ethyl acetate (1:1) to give spirocyclic indolizine (±)-7 as following. (±)-N-benzyl-5',6'-dihydro-2'H-spiro[isoindoline-1,1'-pyrrolo[2,1-a]isoquinoline]-3,3'(10b'H)- dione ((±)-7aA) -S15-

16 The reaction was carried out on pure α-acetoxy lactams (±)-6aA or (±)-6aA. In both cases the same spirocyclic indolizine (±)-6a was isolated as sole diastereoisomer in 80% yield: Mp = C, 1 H NMR (300 MHz, CDCl 3 ): (m, 1H, CH 2 ), (m, 3H, 2 x CH 2 ), (m, 1H, CH 2 ), 4.14 (d, J = 16.0 Hz, 1H, CH 2 ), 4.63 (s, 1H, CH), 5.13 (d, J = 16.0 Hz, 1H, CH 2 ), (m, 1H, H aro ), (m, 2H, H aro ), (m, 7H, H aro ), (m, 1H, H aro ), 7.50 (t, J = 7.3 Hz, 1H, H aro ), 7.64 (d, J = 7.5 Hz, 1H, H aro ) ppm. 13 C NMR (75 MHz, CDCl 3 ): 33.2 (CH 2 ), 39.9 (CH 2 ), 41.6 (CH 2 ), 42.4 (CH 2 ), 64.1 (C q ), 64.8 (CH), (CH aro ), (CH aro ), (CH aro ), (CH aro ), (CH aro ), (2 x CH aro ), (2 x CH aro ), (CH aro ), (CH aro ), (CH aro ), (C q aro), (C q aro), (CH aro ), (C q aro), (C q aro), (C q aro), (C=O), (C=O) ppm. HRMS (+ESI) calculated for C 26 H 23 N 2 O 2 [M+H] + : , found (±)-N-Benzyl-8',9'-dimethoxy-5',6'-dihydro-2'H-spiro[isoindoline-1,1'-pyrrolo[2,1-a]isoquinoline]-3,3'(10b'H)-dione ((±)-7bA) The reaction was carried out on a mixture of two regioisomers of α-acetoxy lactams (±)-6b(A,A ) and (±)-6b(B,B ) (ratio 60:40) and afforded the desired spirocyclic indolizine as a mixture of two regioisomers in 80:20 ratio (±)-7bA/8bB and in an overall yield of 54%. Spirocyclic indolizine (±)- 7bA was isolated as one pure diastereoisomer: this compound was purified by fractional crystallization from dry ethanol; R f (cyclohexane/acoet: 2/3)= 0.23; IR (ATR): , , Mp = C; 1 H NMR (300 MHz, CDCl 3 ): 2.45 (d, J = 16.0 Hz, 1H, CH 2 ), (m, 1H, CH 2 ), (m, 2H, CH 2 ), 3.17 (d, J = 16.0 Hz, 1H, CH 2 ), 3.54 (s, 3H, OCH 3 ), 3.72 (s, 3H, OCH 3 ), (m, 1H, CH 2 ), 4.97 (d, J = 16.0 Hz, 1H, CH 2 ), 5.16 (d, J = 16.0 Hz, 1H, CH 2 ), 5.24 (s, 1H, CH), 5.94 (s, 1H, H aro ), 6.38 (s, 1H, H aro ), (m, 1H, H aro ), (m, 5H, H aro ), (m, 2H, H aro ), 7.74 (d, J = 7.0 Hz, 1H, H aro ) ppm. 13 C NMR (75 MHz, CDCl 3 ): 28.2 (CH 2 ), 36.7 (CH 2 ), 39.7 (CH 2 ), 43.6 (CH 2 ), 55.6 (OCH 3 ), 55.8 (OCH 3 ), 58.9 (CH), 70.1 (C q ), (CH aro ), (CH aro ), (CH aro ), (C q aro), (CH aro ), (C q aro), (CH aro ), (2 x CH aro ), (CH aro ), (2 x CH aro ), (C q aro), (CH aro ), (C q aro), (C q aro), (C q aro), (C q aro), (C=O), (C=O) ppm. HRMS (+ESI) calculated for C 28 H 27 N 2 O 4 [M+H] + : , found X. General procedure for -cationic cyclization of α-hydroxy lactams (±)-11 A solution of spiro-hydroxy lactams (±)-11a-b(B,B ) as a mixture of two diastereoisomers (0.7 mmol) in 2 ml trifluoroacetic acid was stirred at room temperature for 24 h. The reaction mixture was then diluted carefully with water (10 ml) and extracted twice with dichloromethane (20 ml). -S16-

17 The organic layer was neutralized with a cold 10% NaHCO 3 aqueous solution, dried over MgSO 4 and evaporated in vacuo to give an oil residue which was purified by flash column chromatography on silica gel column using cyclohexane and ethyl acetate (1:1) to give spirocyclic isoindoles (±)-8 as following. N-Benzyl-5',6'-dihydro-1'H-spiro[isoindoline-1,2'-pyrrolo[2,1-a]isoquinoline]-3,3'(10b'H)-dione ((±)-8a(B,B )) This product was obtained as separable two diastereisomers. Major diastereoisomer (±)-8a(B): This compound was isolated by flash chromatography, Mp = C; IR (ATR): cm -1 ; 1 H NMR (300 MHz, CDCl 3 ): 2.49 (dd, 1H, J = 7, 14 Hz, CH 2 ), (m, 2H, CH 2 ), (m, 2H, CH 2 ), (m, 1H, CH 2 ), 4.50 (d, J = 16.0 Hz, 1H, CH 2 ), 4.75 (t, J = 7.0 Hz, 1H, CH), 5.17 (d, J = 16.0 Hz, 1H, CH 2 ), (m, 2H, H aro ), (m, 10H, H aro ), 7.93 (d, J = 8.0 Hz, 1H, H aro ) ppm. 13 C NMR (75 MHz, CDCl 3 ): 28.3 (CH 2 ), 37.2 (CH 2 ), 38.2 (CH 2 ), 44.5 (CH 2 ), 53.6 (CH), 71.4 (C q ), (CH aro ), (CH aro ), (CH aro ), (CH aro ), (CH aro ), (2 x CH aro ), (CH aro ), (2 x CH aro ), (CH aro ), (CH aro ), 131.5(C q aro), (CH aro ), (C q aro), (C q aro), (C q aro), (C q aro), (C=O), (C=O). HRMS (+ESI) calculated for C 26 H 23 N 2 O 2 [M+H] + : , found Minor diastereoisomer (±)-8a(B ): This compound was purified by fractional crystallization from dry ethanol; R f (cyclohexane/acoet: 2/3) = 0.43; IR (ATR): cm -1 ; Mp = C. 1 H NMR (300 MHz, CDCl 3 ): 2.30 (dd, J = 8.5, 13.3 Hz, 1H, CH 2 ), 2.82 (dd, J = 7.3, 13.3 Hz, 1H, CH 2 ), (m, 1H, CH 2 ), (m, 1H, CH 2 ), (m, 1H, CH 2 ), 4.08 (d, J = 16 Hz, 1H, CH 2 ), (m, 1H, CH 2 ), 5.16 (t, J = 7.8 Hz, 1H, CH), 5.22 (d, J = 16 Hz, 1H, CH 2 ), (m, 1H, H aro ), (m, 4H, H aro ), (m, 4H, H aro ), (m, 3H, H aro ), 7.96 (d, 1H, J= 7.0 Hz, H aro ) ppm. 13 C NMR (75 MHz, CDCl 3 ): 28.4 (CH 2 ), 36.6 (CH 2 ), 38.5 (CH 2 ), 44.5 (CH 2 ), 53.3 (CH), 72.0 (C q ), (CH aro ), (CH aro ), (CH aro ), (CH aro ), (CH aro ), (2 x CH aro ), (2 x CH aro ), (CH aro ), (CH aro ), (C q aro), (CH aro ), (C q aro), (C q aro), (C q aro), (C q aro), (C=O), (C=O) ppm. HRMS (+ESI) calculated for C 26 H 23 N 2 O 2 [M+H] + : , found N-Benzyl-8',9'-dimethoxy-5',6'-dihydro-1'H-spiro[isoindoline-1,2'-pyrrolo[2,1-a]isoquinoline]- 3,3'(10b'H)-dione (±)-8b(B,B ) -S17-

18 Spirocyclic indolizine (±)-8b(B,B ): These products were obtained as a mixture of inseparable two diastereoisomers (d.r. 75:25 ). Major diastereoisomer (±)-8bB: The NMR characteristics of this product were extracted from the spectrum of the mixture; R f (cyclohexane/acoet: 1/4) = 0.37; IR (ATR): , cm -1 ; 1 H NMR (300 MHz, CDCl 3 ): 2.27 (dd, J = 8.0, 13.0 Hz, 1H, CH 2 ), (m, 2H, CH 2 ), (m, 1H, CH 2 ), (m, 1H, CH 2 ), 3.73 (s, 3H, OCH 3 ), 3.93 (s, 3H, OCH 3 ), 4.00 (d, J = 16.0 Hz, 1H, CH 2 ), (m, 1H, CH 2 ), 5.08 (t, J = 8.0 Hz, 1H, CH), 5.26 (d, J = 16 Hz, 1H, CH 2 ), 6.27 (s, 1H, H aro ), 6.69 (s, 1H, H aro ), (m, 4H, H aro ), (m, 2H, H aro ), (m, 2H, H aro ), (m, 1H, H aro ) ppm. 13 C NMR (75 MHz, CDCl 3 ): 27.9 (CH 2 ), 36.6 (CH 2 ), 38.6 (CH 2 ), 44.5 (CH 2 ), 53.1 (OCH 3 ), 55.9 (OCH 3 ), 56.0 (CH), 72.0 (C q ), (CH aro ), (CH aro ), (CH aro ), (CH aro ), (C q aro), (CH aro ), (CH aro ), (2 x CH aro ), (C q aro), (2 x CH aro ), (C q aro), (CH aro ), (C q aro), (C q aro), (C q aro), (C q aro), (C=O), (C=O) ppm. Minor diastereoisomer (±)-8bB : The NMR characteristics of this product were extracted from the spectrum of the mixture: 1 H NMR (300 MHz, CDCl 3 ): 2.46 (dd, J = 6.0, 14.0 Hz, 1H, CH 2 ), (m, 2H, CH 2 ), (m, 2H, CH 2 ), 3.80 (s, 3H, OCH 3 ), 3.91 (s, 3H, OCH 3 ), (m, 1H, CH 2 ), 4.48 (d, J = 16.0 Hz, 1H, CH 2 ), 4.73 (t, J = 7.0 Hz,1H, CH), 5.16 (d, J = 16.0 Hz, 1H, CH 2 ), 6.40 (s, 1H, H aro ), 6.67 (s, 1H, H aro ), (m, 1H, H aro ), (m, 4H, H aro ), (m, 3H, H aro ), (m, 1H, H aro ) ppm. 13 C NMR (75 MHz, CDCl 3 ): 27.8 (CH 2 ), 37.0 (CH 2 ), 38.4 (CH 2 ), 44.5 (CH 2 ), 53.4 (OCH 3 ), 55.9 (OCH 3 ), 56.0 (CH), 71.4 (C q ), (CH aro ), (CH aro ), (CH aro ), (CH aro ), (C q aro), (CH aro ), (C q aro), (2 x CH aro ), (CH aro ), (2 x CH aro ), (C q aro), (CH aro ), (C q aro), (C q aro), (2 x C q aro), (C=O), (C=O) ppm. HRMS (+ESI) calculated for C 28 H 27 N 2 O 4 [M+H] + : , found S18-

19 XI. Copies of 1 H and 13 C NMR spectra for all new compounds (±)-10a (±)-10a -S19-

20 (±)-10b (±)-10b -S20-

21 (±)-10c (±)-10c -S21-

22 (±)-6a(A,A ) 60% (±)-6a(B,B ) 40% Maj (±)-6a(A) -S22-