Programmable Enantioselective One-pot Synthesis of Molecules With Eight. Stereocenters

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1 Programmable Enantioselective ne-pot Synthesis of Molecules With Eight Stereocenters Marco Potowski 1,2, Markus Schürmann 3, ans Preut 3, Andrey P. Antonchick 1* and erbert Waldmann 1,2* 1) Max-Planck-Institut für Molekulare Physiologie, Abteilung Chemische Biologie, tto-ahn-strasse 11, Dortmund, Germany 2) Technische Universität Dortmund, akultät Chemie, Chemische Biologie, tto- ahn-strasse 6, Dortmund, Germany 3) Technische Universität Dortmund, akultät Chemie, Anorganische Chemie, tto- ahn-strasse 6, Dortmund, Germany and 1

2 Table of Contents Supplementary Results Supplementary igures Supplementary Tables Supplementary Methods 15 Synthesis of α-iminoesters 16 General procedure of 1,3-dipolar cycloaddition of azomethine ylides with 1,4-benzoquinone (a) Procedure for the synthesis of the anti-regioisomers 24 Characterization of the anti-regioisomers (3a 3h) 25 NMR-spectra of the anti-regioisomers (3a 3h) 30 (b) Procedure for the synthesis of the mono addition products 38 Characterization of the mono addition products (6a 6l) 39 NMR-spectra and PLC chromatograms of the mono addition products (6a 6l) 47 (c) Procedure A 71 Characterization of the chiral syn-regioisomers (4a 4l) 72 NMR-spectra of the chiral syn-regioisomers (4a 4l) 80 (d) Procedure B 92 Characterization of the chiral mixed syn-regioisomers (8a 8i) 93 NMR-spectra of the chiral mixed syn-regioisomers (8a 8i) 100 (e) Procedure C 109 Characterization of the mixed chiral anti-regioisomers (9a 9l) 110 NMR-spectra and PLC chromatograms of the mixed chiral anti-regioisomers (9a 9l) 120 2

3 Supplementary Results Supplementary igures Supplementary igure 1. RTEP plot of anti-regioisomer 3a at the 50% probability level. See Supplementary Table 8 for additional details. Crystallographic data have been deposited at the Cambridge Crystallographic Data Centre and copies can be obtained on request, free of charge, by quoting the publication citation and the deposition number CCDC

4 Supplementary igure 2. RTEP plot of syn-regioisomer 4a at the 50% probability level. See Supplementary Table 9 for additional details. Crystallographic data have been deposited at the Cambridge Crystallographic Data Centre and copies can be obtained on request, free of charge, by quoting the publication citation and the deposition number CCDC

5 Br N N anti-9 (rac) Br N N anti-9 98% ee Br N N anti-9 95% ee Supplementary igure 3. Reverse mixed asymmetric 1,3-dipolar cycloaddition of azomethine ylides to obtain the two different anti-9 enantiomers. 5

6 Supplementary Tables Supplementary Table 1. ptimization of the reaction conditions for the catalytic 1,3-dipolar cycloaddition of benzoquinone 1 with azomethine ylides. See Supplementary Methods for additional details. Entry * catalyst Catalyst (mol%) Base Solvent Time r.r. (3a:4a) d.r. Yield [%] 1 Cu(C 3 CN) 4 P 6 5 Et 3 N DCM 10 min 50:50 >95: Cu(C 3 CN) 4 P 6 5 Et 3 N PhMe 24 h n.d. n.d. trace 3 Cu(C 3 CN) 4 P 6 5 Et 3 N Et 2 24 h n.d. n.d. trace 4 Cu(C 3 CN) 4 P 6 5 Et 3 N T 10 min 75:25 >95: Cu(C 3 CN) 4 P 6 5 Et 3 N EtAc 1 h 34:66 >95: Cu(C 3 CN) 4 P 6 5 Et 3 N C 3 CN 1 h n.d. n.d. n.d. 7 Cu(C 3 CN) 4 P 6 5 Et 3 N Me 10 min n.d. n.d. n.d. 8 Cu(C 3 CN) 4 P 6 5 Et 3 N CCl 3 10 min 50:50 >95: Cu(C 3 CN) 4 P 6 5 Et 3 N 1,4-Dioxane 1 h 75:25 >95: Cu(C 3 CN) 4 P 6 5 Et 3 N 1,2-Dichloroethane 10 min 50:50 >95: Cu(C 3 CN) 4 B 4 5 Et 3 N T 30 min 80:20 >95:5 87 (65 ) 12 CuTf 0.5PhMe 5 Et 3 N T 3 h 80:20 >95: AgAc 5 Et 3 N T 1 h n.d. n.d. n.d. 14 AgTA 5 Et 3 N T 1 h n.d. n.d. n.d. 15 AgTf 5 Et 3 N T 1 h n.d. n.d. n.d. 16 AgSb 6 5 Et 3 N T 1 h n.d. n.d. n.d. 17 Cu(C 3 CN) 4 B 4 5 DIPEA T 1 h n.d. n.d. trace 18 Cu(C 3 CN) 4 B 4 5 DMAP T 1 h n.d. n.d. trace 19 Cu(C 3 CN) 4 B 4 5 DBU T 15 min n.d. n.d Cu(C 3 CN) 4 B 4 5 NaMe T 1h n.d. n.d. trace * Reaction conditions: catalyst, base (20 mol%, 0.06 mmol), iminoester 2a (2.2 equiv., 0.66 mmol) and 1,4-benzoquinone 1 (1 equiv., 0.30 mmol), ambient temperature. Determined by 1 NMR spectroscopy. Yields of the regioisomeric mixture of 3a and 4a after column chromatography. Yield for the pure regioisomer 3a. r.r. regioisomer ratio, d.r. diastereomer ratio, n.d. not determinated. 6

7 Supplementary Table 2. Selective catalytic synthesis of the anti-regioisomers 3. * *The reactions were carried out with 0.30 mmol of 1 and 0.66 mmol of 2 in T (0.1M). Isolated yields of the pure major regioisomer. Determined by 1 -NMR spectroscopy. r.r. regioisomer ratio, d.r. diastereomer ratio. 7

8 Supplementary Table 3. ptimization of the reaction conditions for the enantioselective 1,3-dipolar cycloaddition of benzoquinone 1 with azomethine ylides. See Supplementary Methods for additional details. Br Br Br Br 1 + N metal salt ligand 7 base solvent N N + N N 2a Br anti-3a syn-4a N PPh 2 PR 2 2 NMe 2 PCy 2 R= PPh 2 PPh 2 PPh PPh 2 2 PR 2 e e e 7a 7b 7c 7d 7e S-t-Bu PPh 2 N PPh 2 NMe2 PR 2 Ph 7j R= e P-t-Bu 2 PCy 2 e PPh 2 e PPh 2 Ph 2 P Me 2 N e Ph R 2 P e NMe 2 Ph C 3 Ph 7f 7g 7h 7i Me 2 N 7k R= C 3 Entry * catalyst Catalyst Ligand Time r.r. Ligand Base Solvent d.r. Yield e.e. (mol%) (mol%) [h] (3a:4a) [%] 1 Cu(C 3 CN) 4 P 6 6 7a 6 Et 3 N T 20 34:66 >95: Cu(C 3 CN) 4 P 6 6 7b 6 Et 3 N T 48 n.d. n.d. trace n.d. 3 Cu(C 3 CN) 4 P 6 6 7c 6 Et 3 N T 20 50:50 >95: Cu(C 3 CN) 4 P 6 6 7d 6 Et 3 N T 20 50:50 >95: Cu(C 3 CN) 4 P 6 6 7e 6 Et 3 N T 48 n.d. n.d. trace n.d. 6 Cu(C 3 CN) 4 P 6 6 7f 6 Et 3 N T 48 n.d. n.d. trace n.d. 7 Cu(C 3 CN) 4 P 6 6 7g 6 Et 3 N T 1 12:88 >95: Cu(C 3 CN) 4 P 6 6 7h 6 Et 3 N T 48 n.d. n.d. trace n.d. 9 Cu(C 3 CN) 4 P 6 6 7i 6 Et 3 N T 6 12:88 >95: Cu(C 3 CN) 4 P 6 6 7j 6 Et 3 N T 16 34:66 >95: Cu(C 3 CN) 4 P 6 6 7k 6 Et 3 N T 16 34:66 >95: Cu(C 3 CN) 4 P 6 3 7g 3 Et 3 N T 2 8:92 >95: Cu(C 3 CN) 4 P 6 1 7g 1 Et 3 N T 24 n.d. n.d Cu(C 3 CN) 4 Tf 3 7g 3 Et 3 N T 40 50:50 >95: Cu(C 3 CN) 4 B 4 3 7g 3 Et 3 N T 16 6:94 >95: Cu(Tf) 2 3 7g 3 Et 3 N T 40 50:50 >95: Cu(C 3 CN) 4 B 4 3 7g 3 Et 3 N DCM 4 25:75 >95: Cu(C 3 CN) 4 B 4 3 7g 3 Et 3 N PhMe 4 5:95 >95: Cu(C 3 CN) 4 B 4 3 7g 3 Et 3 N CCl 3 4 4:96 >95: Cu(C 3 CN) 4 B 4 3 7g 3 DIPEA PhMe 16 6:94 >95: * Reaction conditions: ligand 7a-k, catalyst, base (20 mol%, 0.06 mmol), iminoester 2a (2.2 equiv., 0.66 mmol) and 1,4-benzoquinone 1 (1 equiv., 0.30 mmol), ambient temperature. Determined by 1 NMR spectroscopy. Isolated yields of the major regioisomer 4a after column chromatography. Determined by PLC analysis on chiral phase for the single addition products 6. opposite enantiomer. r.r. regioisomer ratio, d.r. diastereomer ratio, n.d. not determinated. 8

9 Supplementary Table 4. Selective synthesis of the mono addition products 6* S-t-Bu R 1 e PPh 2 R N R 2 3 mol%(r)-esulphos 7g 3mol%Cu(C 3 CN) 4 B 4 20 mol% DIPEA toluene, rt, 16 h 6 N R 2 2 Br N N N N 6a 62% yield e.e. = 98% 6b 57% yield e.e. = 97% 6c 68% yield e.e. = 98% 6d 59% yield e.e. = 98% N N N N 6e 46% yield e.e. = 97% 6f 78% yield e.e. = 98% 6g 74% yield e.e. = 98% 6h 80% yield e.e. = 98% Br Br Cl N N N N Ph 6i 31% yield e.e. = 96% 6j 56% yield e.e. = 99% 6k 66% yield e.e. = 98% 6l 80% yield e.e. = 98% *The reactions were carried out with 0.30 mmol of 1 and 0.33 mmol of 2 in 3 ml toluene. Isolated yields after column chromatography. Determined by PLC analysis on chiral phase. 9

10 Supplementary Table 5. Enantioselective synthesis of the chiral syn-regioisomers 4.* S-t-Bu 1 + R 1 N R 2 e 3 mol%(r)-esulphos 7g 3mol%Cu(C 3 CN) 4 B 4 20 mol% DIPEA toluene, rt, 16 h PPh 2 R 2 N R 1 R 1 N R 2 + N R 2 R 1 R 1 N R minor 4 major Br Br N N N N N N 4a 65% yield r.r. > 94:6 d.r. > 95:5 e.e. = 98% 4b 54% yield r.r. > 94:6 d.r. > 95:5 e.e. = 97% 4c 42% yield r.r. > 94:6 d.r. > 95:5 e.e. = 98% N N N N N N 4d 4e 4f 65% yield r.r. = 94:6 d.r. > 95:5 e.e. = 98% 65% yield r.r. = 94:6 d.r. > 95:5 e.e. = 97% 73% yield r.r. = 94:6 d.r. > 95:5 e.e. = 98% Cl Cl N N N N N N 4g 4h 4i 79% yield r.r. = 94:6 d.r. > 95:5 e.e. = 98% 84% yield r.r. = 94:6 d.r. > 95:5 e.e. = 98% 41% yield r.r. = 94:6 d.r. > 95:5 e.e. = 96% Br Br Br Br N N N N N N 4j 4k Ph 4l Ph 66% yield r.r. = 94:6 d.r. > 95:5 e.e. = 99% 38% yield r.r. = 94:6 d.r. > 95:5 e.e. = 98% 54% yield r.r. = 94:6 d.r. > 95:5 e.e. = 98% *The reactions were carried out with 0.30 mmol of 1 and 0.66 mmol of 2 in toluene (0.1M). Isolated yields of the pure major regioisomer after column chromatography. Determined by 1 -NMR spectroscopy. Determined by PLC analysis on chiral phase. r.r. regioisomer ratio, d.r. diastereomer ratio. 10

11 Supplementary Table 6. Enantioselective synthesis of the chiral mixed synregioisomers 8.* 1. 1 N R 1 R 2 1equiv. 2 3mol%Cu(C 3 CN) 4 B 4 3mol%(R)-eSulPhos 7g 20 mol% DIPEA toluene, rt, 1 h 2. N R 3 R equiv. 2 rt, 15 h N R 4 R 3 8 major R 1 N R 2 + R 4 N R 3 9 minor R 1 N R 2 Br Br N N N N N N 8a 8b 8c 51% yield r.r. = 94:6 d.r. > 95:5 e.e. = 98% 56% yield r.r. = 94:6 d.r. > 95:5 e.e. = 98% 34% yield r.r. = 94:6 d.r. > 95:5 e.e. = 98% Br Br Br N N N N N N 8d Ph 8e Ph 8f Ph 70% yield r.r. = 94:6 d.r. > 95:5 e.e. = 98% 64% yield r.r. = 94:6 d.r. > 95:5 e.e. = 98% 72% yield r.r. = 94:6 d.r. > 95:5 e.e. = 98% Br Br Br Cl N N N N N N 8g Ph 8h Ph 8i Ph 64% yield r.r. = 94:6 d.r. > 95:5 e.e. = 98% 57% yield r.r. = 94:6 d.r. > 95:5 e.e. = 98% 70% yield r.r. = 94:6 d.r. > 95:5 e.e. = 98% *The reactions were carried out with 0.30 mmol of 1 and 0.66 mmol of 2 in toluene (0.1M). Isolated yields of the pure major regioisomer after column chromatography. Determined by 1 -NMR spectroscopy. Determined by PLC analysis on chiral phase. r.r. regioisomer ratio, d.r. diastereomer ratio. 11

12 Supplementary Table 7. Enantioselective synthesis of the mixed chiral antiregioisomers 9.* *The reactions were carried out with 0.30 mmol of 1 and 0.66 mmol of 2 in toluene-t mixture (1:2.5). Isolated yields of the pure major regioisomer after column chromatography. Determined by 1 -NMR spectroscopy. Determined by PLC analysis on chiral phase. r.r. regioisomer ratio, d.r. diastereomer ratio. 12

13 Supplementary Table 8. Crystallographic statistics for 3a (CCDC ). See Supplementary Methods for additional details. Compound 3a ormula C Br 2 N 2 6 ormula weight [g mol -1 ] Temperature [K] 173(2) Wave length [Å] Space group P-1 Cell dimensions a, b, c (Å) 6.61, 8.85, α, β, γ ( ) 72.81, 80.07, Volume [Å 3 ] (7) Z 1 R-actor% 3.03 Calc. density [Mg m 3 ] Θ(max) [ ] 25.5 Θ(min) [ ] 2.5 (000) 328 Index ranges -8 h 8-10 k l 15 Reflections collected 8625 Independent reflections 2476 [R(int) = 0.035] R[ 2 > 2σ( 2 )] wr( 2 ) S

14 Supplementary Table 9. Crystallographic statistics for 4a (CCDC ). See Supplementary Methods for additional details. Compound 4a ormula C Br 2 N 2 6 ormula weight [g mol -1 ] Temperature [K] 291(2) Wave length [Å] Space group P2 1 Cell dimensions a, b, c (Å) 10.16, 10.25, α, β, γ ( ) 90.00, , Volume [Å 3 ] (18) Z 2 R-actor% 2.98 Calc. density [Mg m 3 ] Θ(max) [ ] 25.5 Θ(min) [ ] 2.1 (000) 656 Index ranges -12 h k l 16 Reflections collected Independent reflections 5045 [R(int) = 0.045] R[ 2 > 2σ( 2 )] wr( 2 ) S

15 Supplementary Methods: Chemistry Unless otherwise noted, all commercially available compounds were used as provided without further purifications. Dry solvents (T, toluene) were used as commercially available; C 2 Cl 2 was purified by the Solvent Purification System M-BRAUN Glovebox Technology SPS-800. Solvents for chromatography were technical grade. Analytical thin-layer chromatography (TLC) was performed on Merck silica gel aluminium plates with -254 indicator. Compounds were visualized by irradiation with UV light or potassium permanganate staining. Column chromatography was performed using silica gel Merck 60 (particle size mm). Solvent mixtures are understood as volume/volume. 1 -NMR and 13 C-NMR were recorded on a Bruker DRX400 (400 Mz), Bruker DRX500 (500 Mz) and INVA500 (500 Mz) using CDCl 3 or (CD 3 ) 2 S as solvent. Data are reported in the following order: chemical shift (δ) values are reported in ppm with the solvent resonance as internal standard (CDCl 3 : δ = 7.26 ppm for 1, δ = ppm for 13 C; (CD 3 ) 2 S: δ = 3.30 ppm for 1, δ = ppm for 13 C); multiplicities are indicated br s (broadened singlet), s (singlet), d (doublet), t (triplet), q (quartet) m (multiplet); coupling constants (J) are given in ertz (z). igh resolution mass spectra were recorded on a LTQ rbitrap mass spectrometer coupled to an Acceka PLC-System (PLC column: ypersyl GLD, 50 mm x 1 mm, particle size 1.9 µm, ionization method: electron spray ionization). ourier transform infrared spectroscopy (T-IR) spectra were obtained with a Bruker Tensor 27 spectrometer (ATR, neat) and are reported in terms of frequency of absorption (cm -1 ). ptical rotations were measured in a Schmidt + aensch Polartronic 8 polarimeter. The enantiomeric excesses were determined by PCL analysis using a chiral stationary phase column (column: CIRALCEL IA, eluent: (DCM/Et = 100/2) / iso-hexane). The chiral PLC methods were calibrated with the corresponding racemic mixtures. The ratio of regioisomers and diastereomers was determined by 1 -NMR analysis via integration of 15

16 characteristic signals of methyl esters. Chemical yields refer to pure isolated substances. Yields and enantiomeric excesses, diastereoselectivity and regioselectivity are given in the tables. The chemicals and solvents were purchased from the companies Sigma-Aldrich, Acros rganic, ABCR and Alfa Aesar. (R p )-2-(tert-Butylthio)-1-(diphenyl-phosphino)ferrocene (purity: 98%), Tetrakis(acetonitrile)copper(I) hexafluorophosphate (purity; 97%) and Tetrakis(acetonitrile)copper(I) tetrafluoroborate (purity: 97%) were purchased from Sigma- Aldrich. Synthesis of α-iminoesters 1,2 To the suspension of amino acid ester hydrochloride (1.2 equiv., 12 mmol) and MgS 4 (1.25 equiv., 12.5 mmol) in DCM (15 ml) was added Et 3 N (1.2 equiv., 12 mmol). The mixture was stirred at ambient temperature for 1h. Then the corresponding aldehyde (1 equiv., 10 mmol) was added and the mixture was allowed to stir at ambient temperature overnight. The precipitate was removed by filtration and the filtrate was washed with water (15 ml). The aqueous phase was extracted two times with DCM (10 ml) and the combined organic layer was washed once with brine (15 ml), dried over MgS 4 and concentrated. The iminoesters were used for 1,3-dipolar cycloadditions and NMR studies without further purification. Methyl (E)-N-[(p-bromophenyl)methylene]alaninate (2a) 3 16

17 86% yield; 1 NMR (400 Mz, CDCl 3 ): δ 8.25 (s, 1), 7.64 (d, J = 8.4 z, 2), 7.54 (d, J = 8.4 z, 2), 4.15 (q, J = 6.8 z, 1), 3.74 (s, 3), 1.52 (d, J = 6.8 z, 3); 13 C NMR (101 Mz, CDCl 3 ): δ , , , , , , 68.05, 52.41, Methyl (E)-N-[(4-methylphenyl)methylene]alaninate (2b) 84% yield; 1 NMR (400 Mz, CDCl 3 ): δ 8.26 (s, 1), 7.66 (d, J = 8.0 z, 2), 7.21 (d, J = 8.0 z, 2), 4.13 (q, J = 6.8 z, 1), 3.73 (s, 3), 2.37 (s, 3), 1.52 (d, J = 6.8 z, 3); 13 C NMR (101 Mz, CDCl 3 ): δ , , , , , , 68.14, 52.29, 21.63, Methyl (E)-N-[p-methoxyphenyl)methylene]alaninate (2c) 3,4 66% yield; 1 NMR (400 Mz, (CD 3 ) 2 S): δ 8.30 (s, 1), 7.68 (d, J = 8.8 z, 2), 6.99 (d, J = 8.8 z, 2), 4.15 (q, J = 6.8 z, 1), 3.79 (s, 3), 3.62 (s, 3), 1.35 (d, J = 6.8 z, 3); 13 C NMR (101 Mz, (CD 3 ) 2 S): δ , , , , , , 66.62, 55.32, 51.83, Methyl (E)-N-[(p-fluorophenyl)methylene]alaninate (2d) 3 70% yield; 1 NMR (400 Mz, (CD 3 ) 2 S): δ 8.40 (s, 1), (m, 2), (m, 2), 4.21 (q, J = 6.8 z, 1), 3.63 (s, 3), 1.37 (d, J = 6.8 z, 3); 13 C NMR (101 Mz, (CD 3 ) 2 S): δ , (d, J = z), , (d, J = 2.9 z), (d, J = 8.9 z), (d, J = 21.9 z), 66.50, 51.90,

18 Methyl (E)-N-[(m-fluorophenyl)methylene]alaninate (2e) 92% yield; 1 NMR (400 Mz, (CD 3 ) 2 S): δ 8.41 (s, 1), 7.59 (d, J = 7.7 z, 1), (m, 2), (m, 1), 4.24 (q, J = 6.8 z, 1), 3.64 (s, 3), 1.38 (d, J = 6.8 z, 3); 13 C NMR (101 Mz, (CD 3 ) 2 S): δ , (d, J = z), (d, J = 2.8 z), (d, J = 7.4 z), (d, J = 8.2 z), (d, J = 2.7 z), (d, J = 21.4 z), (d, J = 22.2 z), 66.44, 51.94, Methyl (E)-N-[(o-fluorophenyl)methylene]alaninate (2f) 81% yield; 1 NMR (400 Mz, (CD 3 ) 2 S): δ 8.63 (s, 1), (m, 1), (m, 1), (m, 2), 4.32 (q, J = 6.8 z, 1), 3.64 (s, 3), 1.38 (d, J = 6.8 z, 3); 13 C NMR (101 Mz, (CD 3 ) 2 S): δ , (d, J = z), (d, J = 4.4 z), (d, J = 8.8 z), (d, J = 2.7 z), (d, J = 3.4 z), (d, J = 9.3 z), (d, J = 20.8 z), 66.81, 51.94, Methyl (E)-N-benzylidenealaninate (2g) 4,6 61% yield; 1 NMR (400 Mz, (CD 3 ) 2 S): δ 8.42 (s, 1), 7.76 (d, J = 7.7 z, 2), (m, 3), 4.23 (q, J = 6.7 z, 1), 3.65 (s, 3), 1.39 (d, J = 6.7 z, 3); 13 C NMR (101 Mz, (CD 3 ) 2 S): δ , , , , , , 66.65, 51.90,

19 Methyl (E)-N-[2-naphthyl)methylene]alaninate (2h) 2,3 55% yield; 1 NMR (400 Mz, CDCl 3 ): δ 8.47 (s, 1), 8.09 (s, 1), (m, 1), (m, 3), (m, 2), 4.23 (q, J = 6.8 z, 1), 3.77 (s, 3), 1.58 (d, J = 6.8 z, 3); 13 C NMR (101 Mz, CDCl 3 ): δ , , , , , , , , , , , , 68.26, 52.41, Cl N Methyl (E)-N-[(2-chloro,5-fluorophenyl)methylene]alaninate (2i) 85% yield; 1 NMR (500 Mz, (CD 3 ) 2 S): δ 8.59 (s, 1), (m, 1), 7.41 (d, J = 8.1 z, 1), (m, 1), 4.33 (q, J = 6.8 z, 1), 3.67 (s, 3), 1.41 (d, J = 6.8 z, 3); 13 C NMR (126 Mz, (CD 3 ) 2 S): δ , (d, J = z), (d, J = 32.7 z), (d, J = 4.8 z), (d, J = 9.3 z), (d, J = 54.9 z), (d, J = 13.7 z), (d, J = 21.0 z), 67.57, 51.93, Methyl (E)-N-[4-(trifluoromethyl)phenyl)methylene]alaninate (2j) 7 96% yield; 1 NMR (400 Mz, (CD 3 ) 2 S): δ 8.52 (s, 1), 7.96 (d, J = 8.1 z, 2), 7.81 (d, J = 8.1 z, 2), 4.29 (q, J = 6.8 z, 1), 3.64 (s, 3), 1.39 (d, J = 6.8 z, 3); 13 C NMR (101 Mz, (CD 3 ) 2 S): δ , , , (q, J = 31.9 z), , (q, J = 3.7 z), , 66.55, 51.96,

20 Methyl (E)-N-[(o-tolyl)methylene]alaninate (2k) 2 77% yield; 1 NMR (400 Mz, CDCl 3 ): δ 8.62 (s, 1), 7.92 (d, J = 7.4 z, 1), 7.31 (t, J = 7.4 z, 1), 7.23 (t, J = 7.4 z, 1), 7.17 (d, J = 7.4 z, 1), 4.16 (q, J = 6.8 z, 1), 3.75 (s, 3), 2.51 (s, 3), 1.54 (d, J = 6.8 z, 3); 13 C NMR (101 Mz, CDCl 3 ): δ , , , , , , , , 68.62, 52.33, 19.73, Methyl (E)-N-[(p-bromophenyl)methylene]glycinate (2l) 5 60% yield; 1 NMR (400 Mz, CDCl 3 ): δ 8.24 (s. 1), 7.65 (d, J = 8.4 z, 2), 7.55 (d, J = 8.4 z, 2), 4.40 (s, 2), 3.78 (s, 3); 13 C NMR (101 Mz, CDCl 3 ): δ , , , , , , 62.00, Methyl (E)-N-[(p-fluorophenyl)methylene]phenylglycinate (2m) 74% yield; 1 NMR (500 Mz, CDCl 3 ): δ 8.31 (s, 1), (m, 2), 7.51 (d, J = 7.5 z, 2), (m, 2), (m, 1), (m, 2), 5.20 (s, 1), 3.75 (s, 3); 13 C NMR (126 Mz, CDCl 3 ): δ , (d, J = z), , , (d, J = 3.1 z), (d, J = 8.8 z), , , , , , (d, J = 22.0 z), 76.52,

21 Methyl (E)-N-[(p-bromophenyl)methylene]phenylglycinate (2n) 4 81% yield; 1 NMR (400 Mz, CDCl 3 ): δ 8.29 (s, 1), 7.70 (d, J = 8.4 z, 2), 7.55 (d, J = 8.4 z, 2), 7.50 (d, J = 7.2 z, 2), 7.38 (t, J = 7.2 z, 2), 7.32 (t, J = 7.2 z, 1), 5.20 (s, 1), 3.75 (s, 3); 13 C NMR (101 Mz, CDCl 3 ): δ , , , , , , , , , , 76.55, N Methyl (E)-N-[(p-tolyl)methylene]phenylglycinate (2o) 8 83% yield; 1 NMR (500 Mz, CDCl 3 ): δ 8.31 (s, 1), 7.72 (d, J = 8.0 z, 2), 7.52 (d, J = 7.4 z, 2), 7.37 (t, J = 7.4 z, 2), 7.32 (d, J = 7.4 z, 1), 7.22 (d, J = 8.0 z, 2), 5.19 (s, 1), 3.74 (s, 3), 2.39 (s, 3); 13 C NMR (126 Mz, CDCl 3 ): δ , , , , , , , , , , 76.68, 52.60, Methyl (E)-N-[(p-Methoxyphenyl)methylene]phenylglycinate (2p) 7 42% yield; 1 NMR (400 Mz, CDCl 3 ): δ 8.27 (s, 1), 7.78 (d, J = 8.8 z, 2), 7.51 (d, J = 7.3 z, 2), 7.37 (t, J = 7.3 z, 3), 7.32 (d, J = 7.3 z, 1), 6.92 (d, J = 8.8 z, 2), 5.17 (s, 1), 3.84 (s, 3), 3.74 (s, 3); 13 C NMR (101 Mz, CDCl 3 ): δ , , , , , , , , , , 76.65, 55.51,

22 Methyl (E)-N-[2-Naphthyl)methylene]phenylglycinate (2q) 67% yield; 1 NMR (400 Mz, CDCl 3 ): δ 8.50 (s, 1), (m, 2), 7.87 (dd, J = 16.6, 8.0 z, 3), 7.57 (d, J = 7.4 z, 2), (m, 2), 7.40 (t, J = 7.4 z, 2), 7.34 (t, J = 7.4 z, 1), 5.28 (s, 1), 3.77 (s, 3); 13 C NMR (101 Mz, CDCl 3 ): δ , , , , , , , , , , , , , , , , 76.73, Methyl (E)-N-[cyclohexyl)methylene]alaninate (2r) 9 The suspension of alanine methyl ester hydrochloride (1.2 equiv., 12 mmol) in DCM (15 ml) was washed with aqueous ammonia solution (25%, 15 ml) and the organic phase was dried over MgS 4. resh anhydrous MgS 4 and cyclohexanaldehyde (1 equiv., 10 mmol) were added and the mixture was allowed to stir at ambient temperature overnight. The precipitate was removed by filtration and the filtrate was washed with with brine (15 ml). The aqueous phase was extracted two times with DCM (10 ml) and the combined organic layer was dried over MgS 4 and concentrated. The iminoester was used for 1,3-dipolar cycloaddition and NMR studies without further purification. 58% yield; 1 NMR (400 Mz, CDCl 3 ): δ 7.51 (d, J = 5.5 z, 1), 3.85 (q, J = 6.9 z, 1), 3.71 (s, 3), (m, 1), (m, 6), 1.39 (d, J = 6.9 z, 3), (m, 4); 13 C NMR (101 Mz, CDCl 3 ): δ , , 67.98, 52.25, 43.70, 29.68, 26.02, 25.42,

23 References: [1] Cooper, D.M., Grigg, R., ergreaves, S., Kennewell, P. & Redpath, J. Z+Y-Z compounds as potential 1,3-dipoles. Part 44. Asymmetric 1,3-dipolar cycloaddition reactions of imines and chiral cyclic dipolarophiles. Tetrahedron 51, (1995). [2] Cabrera, S., Arrayás, R.G., Martin-Matute, B., Cossio,.P. & Carretero, J.C. CuI- esulphos complexes: efficient chiral catalysts for asymmetric 1,3-dipolar cycloaddition of azomethine ylides. Tetrahedron 63, (2007). [3] Achard, T., Belokon, Y.N., uentes, J.A., North, M. & Parsons T. Influence of aromatic substituents on metal(ii)salen catalyzed, asymmetric synthesis of α-methyl α-amino acids. Tetrahedron 60, (2004). [4] Wang, C.-J., Liang, G., Xue, Z.-Y. & Gao,. ighly enantioselective 1,3-dipolar cycloaddition of azomethine ylides catalyzed by copper(i)/t-biphamphos complexes. J. Am. Chem. Soc. 130, (2008). [5] López-Pérez, A., Adrio, J. & Carretero, J.C. The phenylsulfonyl group as a temporal regiochemical controller in the catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides. Angew. Chem. Int. Ed. 48, (2009). [6] Lopez-Perez, A., Segler, M., Adrio, J. & Carretero, J.C. Silver-catalyzed 1,3-dipolar cycloaddition of azomethine ylides with β-boryl acrylates. J. rg. Chem. 76, (2011). [7] Grigg, R., Gunaratne,.Q.N., Kemp, J. X=Y-Z Systems as Potential 1,3-Dipoles. Part1. Background and Scope. J. Chem. Perkin Soc. Trans. 1, (1984). [8] Duhamel, L., Plaquevent, J.C. Deracemization by enantioselective protonation. Application to an α-amino acid, phenylglycine. rom Bulletin de la Societe Chimique de rance, (1982). [9] Grigg, R., Montgomery, J., Somasunderam, A. X=Y-Z Systems as Potential 1,3- Dipoles. Part 39. Metallo-Azomethin Ylides from Aliphatic Aldimines. acile Regioand Stereo-specific Cycloaddition Reactions. Tetrahedron 48, (1992) 23

24 General procedure of 1,3-dipolare cycloaddition of azomethine ylides with 1,4-benzoquinone (a) Procedure for the synthesis of the anti-regioisomers To the solution of tetrakis(acetonitrile)copper(i) tetrafluoroborate (5 mol%, 15 µmol), α-iminoester 2 (2.2 equiv., 0.66 mmol) and Et 3 N (20 mol%, 60 µmol) in T was added 1,4-benzoquinone 1 (1 equiv., 0.30 mmol). The mixture was allowed to stir at ambient temperature for 30 minutes. The solvent was removed in vacuo and column chromatography on silica gel (ethyl acetate / petroleum ether (40-60 C)) afford the pure product. Additional purification is possible by crystallisation from ethyl acetate / n-pentane. 24

25 Characterization of the anti-regioisomers (3a 3h) rel-(1r,3s,3ar,4ar,5s,7r,7as,8as)-dimethyl 3,7-bis(4-bromophenyl)-1,5-dimethyl-4,8- dioxododecahydropyrrolo[3,4-f]isoindole-1,5-dicarboxylate (3a) 1 NMR (400 Mz, CDCl 3 ): δ 7.44 (d, J = 8.4 z, 4), 7.22 (d, J = 8.4 z, 4), 4.69 (d, J = 8.5 z, 2), 3.72 (dd, J = 9.2, 8.5 z, 2), 3.56 (s, 6), 2.72 (d, J = 9.2 z, 2), 1.48 (s, 6); 13 C NMR (101 Mz, CDCl 3 ): δ , , , , , , 68.82, 62.14, 61.48, 55.93, 52.76, 25.98; T-IR: v ~ = 3339, 1734, 1702, 1403, 1281, 1240, 1186, 1135, 1069, 1006 cm -1 ; RMS: calcd. for [M+] + C Br 2 N 2 6 = , found: ; calcd. for [M+] + C Br 81 BrN 2 6 = , found: ; calcd. for [M+] + C Br 2 N 2 6 = , found: N N rel-(1r,3s,3ar,4ar,5s,7r,7as,8as)-dimethyl 3,7-bis(4-methylphenyl)-1,5-dimethyl-4,8- dioxododecahydropyrrolo[3,4-f]isoindole-1,5-dicarboxylate (3b) 1 NMR (400 Mz, CDCl 3 ): δ 7.15 (d, J = 8.2 z, 4), 7.11 (d, J = 8.2 z, 4), 4.68 (d, J = 8.9 z, 2), 3.62 (dd, J = 9.2, 8.9 z, 2), 3.58 (s, 6), 2.54 (d, J = 9.2 z, 2), 2.31 (s, 25

26 6), 1.39 (s, 6); 13 C NMR (101 Mz, CDCl 3 ): δ , , , , , , 68.45, 63.03, 61.83, 56.77, 52.50, 26.22, 21.23; T-IR: v ~ = 3359, 1748, 1703, 1508, 1432, 1348, 1290, 1189, 1131, 1020 cm -1 ; RMS: calcd. for [M+] + C N 2 6 = ; found: N N rel-(1r,3s,3ar,4ar,5s,7r,7as,8as)-dimethyl 3,7-bis(4-methoxyphenyl)-1,5-dimethyl- 4,8-dioxododecahydropyrrolo[3,4-f]isoindole-1,5-dicarboxylate (3c) 1 NMR (400 Mz, CDCl 3 ): δ 7.18 (d, J = 8.7 z, 4), 6.84 (d, J = 8.7 z, 4), 4.67 (d, J = 8.8 z, 2), 3.78 (s, 6), 3.59 (s, 6), 3.57 (dd, J = 9.0, 8.8 z, 2), 2.59 (d, J = 9.0 z, 2), 2.47 (br s, 2), 1.40 (s, 6); 13 C NMR (101 Mz, CDCl 3 ): δ , , , , , , 68.37, 62.79, 61.79, 56.62, 55.39, 52.54, 26.33; T-IR: v ~ = 3351, 2955, 1734, 1693, 1608, 1510, 1302,1246, 1132, 1032 cm -1 ; RMS: calcd. for [M+] + C N 2 8 = , found: N N 26

27 rel-(1r,3s,3ar,4ar,5s,7r,7as,8as)-dimethyl dioxododecahydropyrrolo[3,4-f]isoindole-1,5-dicarboxylate (3d) 1 NMR (400 Mz, CDCl 3 ): δ (m, 4), (m, 4), 4.70 (d, J = 8.7 z, 2), 3.68 (dd, J = 9.2, 8.7 z, 2), 3.56 (s, 6), 2.66 (d, J = 9.2 z, 2), 2.52 (br s, 2), 1.45 (s, 6); 13 C NMR (101 Mz, CDCl 3 ): δ , , (d, J = z), (d, J = 3.1 z), (d, J = 8.0 z), (d, J = 21.4 z), 68.61, 62.11, 61.57, 56.14, 52.63, 26.08; T-IR: v ~ = 3318, 1738, 1704, 1606, 1508, 1439, 1292, 1219, 1132 cm -1 ; RMS: calcd. for [M+] + C N 2 6 = , found: N N rel-(1r,3s,3ar,4ar,5s,7r,7as,8as)-dimethyl 3,7-bis(4-fluorophenyl)-1,5-dimethyl-4,8-3,7-bis(3-fluorophenyl)-1,5-dimethyl-4,8- dioxododecahydropyrrolo[3,4-f]isoindole-1,5-dicarboxylate (3e) 1 NMR (400 Mz, CDCl 3 ): δ (m, 2), (m, 4), (m, 2), 4.70 (d, J = 8.7 z, 2), 3.77 (dd, J = 9.2, 8.7 z, 2), 3.57 (s, 6), 2.60 (d, J = 9.2 z, 2), 2.31 (br s, 2), 1.44 (s, 6); 13 C NMR (101 Mz, CDCl 3 ): δ , , (d, J = z), (d, J = 7.0 z), (d, J = 8.2 z), (d, J = 2.7 z), (d, J = 21.2 z), (d, J = 22.4 z), 68.58, (d, J = 1.6 z), 61.34, 56.14, 52.56, ; T-IR: v ~ = 3327, 1732, 1706, 1586, 1485, 1434, 1287, 1233, 1171, 1131 cm -1 ; RMS: calcd. for [M+] + C N 2 6 = , found:

28 N N rel-(1r,3s,3ar,4ar,5s,7r,7as,8as)-dimethyl dioxododecahydropyrrolo[3,4-f]isoindole-1,5-dicarboxylate (3f) 1 NMR (500 Mz, CDCl 3 ): δ (m, 2), (m, 2), (m, 2), (m, 2), 4.88 (d, J = 8.5 z, 2), 3.88 (dd, J = 9.4, 8.5 z, 2), 3.51 (s, 6), 2.86 (d, J = 9.4 z, 2), 1.49 (s, 6); 13 C NMR (126 Mz, CDCl 3 ): δ , , (d, J = z), (d, J = 8.2 z), (d, J = 3.7 z), (d, J = 3.2 z), (d, J = 21.4 z), 68.69, 62.02, (d, J = 3.1 z), 54.99, 52.59, 25.43; T-IR: v ~ = 3371, 1746, 1706, 1482, 1360, 1290, 1236, 1164, 1131 cm -1 ; RMS: calcd. for [M+] + C N 2 6 = , found: N N rel-(1r,3s,3ar,4ar,5s,7r,7as,8as)-dimethyl 3,7-bis(2-fluorophenyl)-1,5-dimethyl-4,8-1,5-dimethyl-4,8-dioxo-3,7-diphenyldodeca-hydropyrrolo[3,4-f]isoindole-1,5-dicarboxylate (3g) 1 NMR (400 Mz, CDCl 3 ): δ (m, 8), (m, 2), 4.69 (d, J = 8.9 z, 2), 3.67 (dd, J = 9.2, 8.9 z, 2), 3.54 (s, 6), 2.45 (d, J = 9.2 z, 2), 1.36 (s, 6); 13 C NMR (101 Mz, CDCl 3 ): δ , , , , , , 68.43, 62.82, 61.64, 56.72, 52.52, 26.05; T-IR: v ~ = 3368, 1746, 1703, 1451, 1355, 1289, 1232, 1187, 1130, 1028 cm -1 ; RMS: calcd. for [M+] + C N 2 6 = , found:

29 N N rel-(1r,3s,3ar,4ar,5s,7r,7as,8as)-dimethyl 1,5-dimethyl-3,7-di(naphthalen-2-yl)-4,8- dioxododecahydropyrrolo[3,4-f]isoindole-1,5-dicarboxylate (3h) 1 NMR (400 Mz, CDCl 3 ): δ (m, 8), (m, 4), (m, 2), 4.86 (d, J = 8.8 z, 2), 3.82 (dd, J = 9.3, 8.8 z, 2), 3.36 (s, 6), 2.71 (d, J = 9.3 z, 2), 1.40 (s, 6); 13 C NMR (101 Mz, CDCl 3 ): δ , , , , , , , , , , , , 68.78, 63.09, 61.85, 56.49, 52.43, 25.99; T-IR: v ~ = 3354, 1747, 1706, 1506, 1375, 1280, 1229, 1152, 1126, 1015 cm -1 ; RMS: calcd. for [M+] + C N 2 6 = 591,24896, found: 591,

30 NMR-spectra of the anti-regioisomers (3a 3h) 1 NMR 3a C NMR

31 N N 3b 1 NMR C NMR

32 N N 3c 1 NMR C NMR

33 N N 3d 1 NMR C NMR

34 N N 3e 1 NMR C NMR

35 N N 3f 1 NMR C NMR

36 N N 3g 1 NMR C NMR

37 N N 3h 1 NMR top C NMR

38 (b) Procedure for the synthesis of the mono addition products (R p )-2-(tert-Butylthio)-1-(diphenylphosphino)ferrocene 7g (3 mol%, 9 µmol) and tetrakis- (acetonitrile)copper(i) tetrafluoroborate (3 mol%, 9 µmol) were dissolved in toluene and stirred at ambient temperature for 5 min. To the resulting solution were added α-iminoester 2 (1 equiv., 0.3 mmol), DIPEA (20 mol%, 60 µmol) and 1,4-benzoquinone 1 (1 equiv., 0.3 mmol) and the mixture was allowed to stir at ambient temperature for 1 h. The crude mixture was directly charged onto silica gel and the product was isolated using petroleum ether (40-60 C) / ethyl acetate as eluent. 38

39 Characterization of the mono addition products (6a 6l) Br a 3 7a 1 2 N (1S,3S)-Methyl 3-(4-bromophenyl)-4,7-dihydroxy-1-methylisoindoline-1-carboxylate (6a) 1 NMR (400 Mz, CDCl 3 ): δ 8.02 (br s, 1), 7.46 (d, J = 8.4 z, 2), 7.13 (d, J = 8.4, 2), 6.79 (d, J = 8.5 z, 1), 6.63 (d, J = 8.5 z, 1), 5.46 (s, 1), 3.83 (s, 3), 1.73 (s, 3); 13 C NMR (101 Mz, CDCl 3 ): δ , , , , , , , , , , , 71.24, 64.21, 53.91, 26.94; T-IR: v ~ = 3316, 2928, 2852, 1714, 1497, 1462, 1255, 1107, 1012, 941 cm -1 ; RMS: calcd. for [M+] + C BrN 4 = , found: ; calcd. for [M+] + C BrN 4 = , found: ; [ α ] RT D = -3.9 (Me, c = 1.0); PLC conditions: CIRAPAK IA column, (C 2 Cl 2 /Et = 100/2) / iso-hexane = 50/50, flow rate = 0.5 ml min -1, minor enantiomer: t R = min; major enantiomer: t R = min. N (1S,3S)-Methyl 4,7-dihydroxy-1-methyl-3-p-tolylisoindoline-1-carboxylate (6b) 1 NMR (500 Mz, CDCl 3 ): δ 8.01 (br s, 1), (m, 4), 6.78 (d, J = 8.5 z, 1), 6.64 (d, J = 8.5 z, 1), 5.42 (s, 1), 3.84 (s, 3), 2.34 (s, 3), 1.73 (s, 3); 13 C NMR (126 Mz, CDCl 3 ): δ , , , , , , , , , 39

40 118.48, , 71.21, 64.65, 53.77, 26.80, 21.31; T-IR: v ~ = 3307, 2923, 2853, 1718, 1457, 1253, 1184, 1110, 1021 cm -1 ; RMS: calcd. for [M+] + C N 4 = , found: ; [ α ] RT D = -5.4 (Me, c = 1.0); PLC conditions: CIRAPAK IA column, (C 2 Cl 2 /Et = 100/2) / iso-hexane = 50/50, flow rate = 0.5 ml min -1, minor enantiomer: t R = min; major enantiomer: t R = min. N (1S,3S)-Methyl 4,7-dihydroxy-3-(4-methoxyphenyl)-1-methylisoindoline-1-carboxylate (6c) 1 NMR (500 Mz, CDCl 3 ): δ 7.99 (br s, 1), 7.22 (d, J = 8.6 z, 2), 6.89 (d, J = 8.6 z, 2), 6.78 (d, J = 8.6 z, 1), 6.65 (d, J = 8.6 z, 1), 5.42 (s, 1), 3.84 (s, 3), 3.80 (s, 3), 1.72 (s, 3); 13 C NMR (126 Mz, CDCl 3 ): δ , , , , , , , , , , , 71.09, 64.17, 55.45, 53.79, 26.74; T-IR: v ~ = 2922, 2853, 2323, 1730, 1510, 1460, 1246, 1177, 1031 cm -1 ; RMS: calcd. for [M+] + C N 5 = , found: ; [ α ] RT D = -3.5 (Me, c = 1.0); PLC conditions: CIRAPAK IA column, (C 2 Cl 2 /Et = 100/2) / iso-hexane = 50/50, flow rate = 0.5 ml min -1, minor enantiomer: t R = min; major enantiomer: t R = min. N 40

41 (1S,3S)-Methyl 3-(4-fluorophenyl)-4,7-dihydroxy-1-methylisoindoline-1-carboxylate (6d) 1 NMR (400 Mz, CDCl 3 ): δ 8.02 (br s, 1), (m, 2), (m, 2), 6.79 (d, J = 8.5 z, 1), 6.63 (d, J = 8.5 z, 1), 5.47 (s, 1), 3.83 (s, 3), 1.73 (s, 3); 13 C NMR (101 Mz, CDCl 3 ): δ , (d, J = z), , , , (d, J = 8.2 z), , , , , (d, J = 21.6 z), 71.12, 64.04, 53.87, 26.87; T-IR: v ~ = 3320, 2954, 2853, 1716, 1604, 1502, 1459, 1222, 1110 cm -1 ; RMS: calcd. for [M+] + C N 4 = , found: ; [ α ] RT D = -1.5 (Me, c = 1.0); PLC conditions: CIRAPAK IA column, (C 2 Cl 2 /Et = 100/2) / iso-hexane = 50/50, flow rate = 0.5 ml min -1, minor enantiomer: t R = min; major enantiomer: t R = min. N (1S,3S)-Methyl 3-(3-fluorophenyl)-4,7-dihydroxy-1-methylisoindoline-1-carboxylate (6e) 1 NMR (400 Mz, CDCl 3 ): δ 8.04 (br s, 1), (m, 1), 7.09 (d, J = 7.5 z), (m, 2), 6.80 (d, J = 8.5 z, 1), 6.64 (d, J = 8.5 z, 1), 5.50 (s, 1), 3.84 (s, 3), 1.74 (s, 3); 13 C NMR (101 Mz, CDCl 3 ): δ , (d, J = z), , , (d, J = 8.2 z), (d, J = 16.4 z), (d, J = 2.8), , , (d, J = 21.2 z), (d, J = 21.6 z), 71.23, (d, J = 1.5 z), 53.88, 26.99; T-IR: v ~ = 3301, 2925, 2853, 2628, 2321, 2163, 1730, 1590, 1449, 1247, 1119 cm -1 ; RMS: calcd. for [M+] + C N 4 = , found: ; [ α ] RT D = -3.4 (Me, c = 1.0); PLC conditions: CIRAPAK IA column, (C 2 Cl 2 /Et = 100/2) / iso-hexane = 50/50, flow rate = 0.5 ml min -1, minor enantiomer: t R = min; major enantiomer: t R = min. 41

42 N (1S,3R)-Methyl 3-(2-fluorophenyl)-4,7-dihydroxy-1-methylisoindoline-1-carboxylate (6f) 1 NMR (400 Mz, CDCl 3 ): δ 8.01 (br s, 1), (m, 1), (m, 3), 6.79 (d, J = 8.5 z, 1), 6.63 (d, J = 8.5 z, 1), 5.83 (s, 1), 3.76 (s, 3), 1.74 (s, 3); 13 C NMR (101 Mz, CDCl 3 ): δ , (d, J = z), , , (d, J = 8.4 z), (d, J = 4.0 z), (d, J = 13.0 z), , (d, J = 3.5 z), , , (d, J = 21.8), 71.18, (d, J = 3.5 z), 53.71, 27.00; T-IR: v ~ = 3230, 2925, 2852, 1702, 1587, 1494, 1373, 1265, 1116, 943 cm -1 ; RMS: calcd. for [M+] + C N 4 = , found: ; [ α ] RT D = (Me, c = 1.0); PLC conditions: CIRAPAK IA column, (C 2 Cl 2 /Et = 100/2) / iso-hexane = 50/50, flow rate = 0.5 ml min -1, minor enantiomer: t R = min; major enantiomer: t R = min. N (1S,3S)-Methyl 4,7-dihydroxy-1-methyl-3-phenylisoindoline-1-carboxylate (6g) 1 NMR (400 Mz, CDCl 3 ): δ 8.06 (br s, 1), (m, 3), 7.28 (d, J = 7.9 z, 2), 6.79 (d, J = 8.5 z, 1), 6.64 (d, J = 8.5 z, 1), 5.46 (s, 1), 3.83 (s, 3), 1.73 (s, 3); 13 C NMR (101 Mz, CDCl 3 ): δ , , , , , , , , , , , 71.23, 64.81, 53.84, 26.85; T-IR: v ~ = 3308, 2928, 2851, 2632, 1980, 1714, 1496, 1454, 1254, 1158, 1030, 941 cm -1 ; RMS: calcd. for [M+] + C N 4 = , found: ; [ α ] RT D = -7.4 (Me, c = 1.0); PLC conditions: 42

43 CIRAPAK IA column, (C 2 Cl 2 /Et = 100/2) / iso-hexane = 50/50, flow rate = 0.5 ml min -1, minor enantiomer: t R = min; major enantiomer: t R = min. N (1S,3S)-Methyl 4,7-dihydroxy-1-methyl-3-(naphthalen-2-yl)isoindoline-1-carboxylate (6h) 1 NMR (500 Mz, CDCl 3 ): δ 8.06 (br s, 1), (m, 4), (m, 2), (m, 1), 6.82 (d, J = 8.5 z, 1), 6.65 (d, J = 8.5 z, 1), 5.65 (s, 1), 3.82 (s, 3), 1.77 (s, 3); 13 C NMR (126 Mz, CDCl 3 ): δ , , , , , , , , 128,90, , , , , , , , , 71.35, 64.96, 53.79, 26.96; T-IR: v ~ = 3322, 2923, 2853, 1712, 1497, 1460, 1369, 1258, 1125 cm -1 ; RMS: calcd. for [M+] + C N 4 = , found: ; [ α ] RT D = (Me, c = 1.0); PLC conditions: CIRAPAK IA column, (C 2 Cl 2 /Et = 100/2) / iso-hexane = 45/55, flow rate = 0.5 ml min -1, minor enantiomer: t R = min; major enantiomer: t R = min. Cl N (1S,3R)-Methyl 3-(2-chloro-6-fluorophenyl)-4,7-dihydroxy-1-methylisoindoline-1- carboxylate (6i) 43

44 1 NMR (500 Mz, CDCl 3 ) major rotamer: δ 8.49 (s, 1), 8.23 (s, 1), (m, 2), (m, 1), (m, 1), 6.78 (d, J = 8.2 z, 1), (m, 1), 6.18 (s, 1), 3.85 (s, 3), 1.77 (s, 3); 13 C NMR (126 Mz, CDCl 3 ) major rotamer: δ , (d, J = z), , , (d, J = 10.3 z), (d, J = 3.4 z), , , , , (d, J = 22.5 z), 71.89, 58.65, 53.76, 27.52; T-IR: v ~ = 3239, 2955, 2853, 1692, 1576, 1455, 1299, 1226, 1113, 1020 cm -1 ; RMS: calcd. for [M+] + C ClN 4 = , found: ; calcd. for [M+] + C ClN 4 = , found: ; [ α ] RT D = (Me, c = 1.0); PLC conditions: CIRAPAK IA column, (C 2 Cl 2 /Et = 100/2) / iso-hexane = 50/50, flow rate = 0.5 ml min -1, minor enantiomer: t R = min; major enantiomer: t R = min. N (1S,3S)-Methyl 4,7-dihydroxy-1-methyl-3-(4-(trifluoromethyl)phenyl)isoindoline-1- carboxylate (6j) 1 NMR (500 Mz, CDCl 3 ): δ 7.98 (br s, 1), 7.58 (d, J = 8.0 z, 2), 7.38 (d, J = 8.0 z, 2), 6.80 (d, J = 8.6 z, 1); 6.62 (d, J = 8.6 z, 1), 5.57 (s, 1), 3.82 (s, 3), 1.75 (s, 3); 13 C NMR (126 Mz, CDCl 3 ): δ , , , , , , , (m), , , 71.36, 64.42, 53.83, 27.08; T-IR: v ~ = 3317, 2929, 1712, 1619, 1498, 1461, 1323, 1108, 1018 cm -1 ; RMS: calcd. for [M+] + C N 4 = , found: ; [ α ] RT D = +1.0 (Me, c = 1.0); PLC conditions: CIRAPAK IA column, (C 2 Cl 2 /Et = 100/2) / iso-hexane = 50/50, flow rate = 0.5 ml min -1, minor enantiomer: t R = min; major enantiomer: t R = min. 44

45 Br N (1S,3S)-Methyl 3-(4-bromophenyl)-4,7-dihydroxyisoindoline-1-carboxylate (6k) 1 NMR (500 Mz, CDCl 3 /(CD 3 ) 2 S = 10/1): δ 7.29 (d, J = 8.4 z, 2), 7.01 (d, J = 8.4 z, 2), 6.58 (d, J = 8.6 z, 1), 6.50 (d, J = 8.6 z, 1), 5.35 (s, 1), 5.01 (s, 1), 3.64 (s, 3); 13 C NMR (126 Mz, CDCl 3 /(CD 3 ) 2 S = 10/1): δ , , , , , , , , , , 65.70, 64.12, 52.90; T-IR: v ~ = 3339, 2925, 2851, 1729, 1490, 1463, 1252, 1211, 1010 cm -1 ; LCMS: calcd. for [M+] + C BrN 4 = 364, found: 364; calcd. for [M+] + C BrN 4 = 366, found: 366; [ α ] RT D = 8.6 (Me, c = 1.0); PLC conditions: CIRAPAK IA column, (C 2 Cl 2 /Et = 100/2) / iso-hexane = 75/25, flow rate = 0.5 ml min -1, minor enantiomer: t R = min; major enantiomer: t R = min. Br N (1S,3S)-methyl 3-(4-bromophenyl)-4,7-dihydroxy-1-phenylisoindoline-1-carboxylate (6l) 1 NMR (500 Mz, CDCl 3 ): δ 7.94 (s, 1), 7.48 (d, J = 8.4 z, 2), 7.34 (d, J = 7.6 z, 3), (m, 4), 6.87 (d, J = 8.6 z, 1), 6.73 (d, J = 8.6 z, 1), 5.41 (s, 1), 3.91 (s, 3); 13 C NMR (126 Mz, CDC 3 ): δ , , , , , , , , , , , , , , , 77.97, 64.18, 54.06; T-IR: v ~ = 3326, 2923, 2852, 1703, 1594, 1459, 1270, 1033, 1009, 977 cm -1 ; LCMS: calcd. for [M+] + C BrN 4 = 440, found: 440; calcd. for [M+] + C BrN 4 = 442, found: 442; [ α ] RT D = -5.1 (c = 1.0 in C 2 Cl 2 ); PLC conditions: CIRAPAK IA column, (C 2 Cl 2 /Et = 45

46 100 / 2) / iso-hexane = 40 / 60, flow rate = 0.5 ml min -1, minor enantiomer: t R = min; major enantiomer: t R = min. 46

47 NMR-spectra and PLC chromatograms of the mono addition products (6a 6l) Br N 1 NMR 6a C NMR

48 PLC traces for 6a: racemat top, chiral bottom. 48

49 N 6b 1 NMR C NMR

50 PLC traces for 6b: racemat top, chiral bottom. 50

51 N 6c 1 NMR C NMR

52 PLC traces for 6c: racemat top, chiral bottom. 52

53 N 6d 1 NMR C NMR

54 PLC traces for 6d: racemat top, chiral bottom. 54

55 N 6e 1 NMR C NMR

56 PLC traces for 6e: racemat top, chiral bottom. 56

57 N 6f 1 NMR top C NMR

58 PLC traces for 6f: racemat top, chiral bottom. 58

59 N 6g 1 NMR C NMR

60 PLC traces for 6g: racemat top, chiral bottom. 60

61 N 6h 1 NMR C NMR

62 PLC traces for 6h: racemat top, chiral bottom. 62

63 Cl N 6i 1 NMR C NMR

64 PLC traces for 6i: racemat top, chiral bottom. 64

65 N 6j 1 NMR C NMR

66 PLC traces for 6j: racemat top, chiral bottom. 66

67 Br N 6k 1 NMR C NMR

68 PLC traces for 6k: racemat top, chiral bottom. 68

69 Br N 6l 1 NMR C NMR

70 PLC traces for 6l: racemat top, chiral bottom. 70

71 (c) Procedure A R 1 R 1 R N R 2 3mol%(R)-eSulPhos 7g 3 mol% Cu(C 3 CN) 4 B 4 20 mol% DIPEA toluene, rt, 16 h N R 2 N R (R p )-2-(tert-Butylthio)-1-(diphenylphosphino)ferrocene 7g (3 mol%, 9 µmol) and tetrakis- (acetonitrile)copper(i) tetrafluoroborate (3 mol%, 9 µmol) were dissolved in toluene and stirred at ambient temperature for 5 min. To the resulting solution were added α-iminoester 2 (2.2 equiv., 0.66 mmol), DIPEA (20 mol%., 60 µmol) and 1,4-benzoquinone 1 (1 equiv., 0.30 mmol) and the mixture was allowed to stir at ambient temperature for 16h. The crude mixture was directly charged onto silica gel and the product was purified using petroleum ether (40-60 C) / ethyl acetate as eluent. Yields, enantiomeric excesses, diastereoselectivity and regionselectivity are given in the tables. The enantiomeric excesses were determined after the first cycloaddition, because the first cycloaddition is the enantioselective step and the second cycloaddition is regio- and diastereoselective. Therefore, in parallel to the double cycloaddition, under identical conditions a reaction with 1.1 equivalent of the azomethine ylide was performed, purified and analyzed by PLC. Retention time and PLC methods are reported for the monoaddition products. 71

72 Characterization of the chiral syn-regioisomers (4a 4l) Br Br 6 N 5 4a 7a a 8a 1 2 N dioxododecahydropyrrolo[3,4-f]isoindole-1,7-dicarboxylate (4a) 1 NMR (400 Mz, CDCl 3 ): δ 7.35 (d, J = 8.4 z, 4), 6.98 (d, J = 8.4 z, 4), 4.58 (d, J = 8.0 z, 2), 3.75 (s, 6), (m, 2), 3.30 (d, J = 9.3 z, 2), 2.38 (br s, 2), 1.56 (s, 6); 13 C NMR (101 Mz, CDCl 3 ): δ , , , , , , , 69.69, 62.24, 61.99, 56.25, 52.88, 26.08; T-IR: v ~ = 3325, 2925, 2851, 2163, 1981, 1720, 1487, 1435, 1401, 1375, 1289, 1196, 1139, 1071, 1010 cm -1 ; RMS: calcd. for [M+] + C Br 2 N 2 6 = , found: ; calcd. for [M+] + C Br 81 BrN 2 6 = , found: ; calcd. for [M+] + C Br 2 N 2 6 = , found: ; [ α ] RT D = (c = 1.0 in C 2 Cl 2 ); PLC conditions: CIRALPAK IA column, (C 2 Cl 2 /Et = 100/2) / iso-hexane = 50/50, flow rate = 0.5 ml min -1, minor enantiomer: t R = min; major enantiomer: t R = min. N N (1S,3R,3aS,4aS,5R,7S,7aR,8aR)-Dimethyl (1S,3R,3aS,4aS,5R,7S,7aR,8aR)-Dimethyl 3,5-bis(4 -bromophenyl)-1,7-dimethyl-4,8-3,5-bis(4-methylphenyl)-1,7-dimethyl-4,8- dioxododecahydropyrrolo[3,4-f]isoindole-1,7-dicarboxylate (4b) 72

73 1 NMR (500 Mz, CDCl 3 ): δ (m, 8), 4.61 (d, J = 9.0 z, 2), 3.77 (s, 6), 3.30 (d, J = 9.4 z, 2), 3.23 (dd, J = 9.4, 9.0 z, 2), 2.30 (s, 6), 1.48 (s, 6); 13 C NMR (126 Mz, CDCl 3 ): δ , , , , , , , 69.18, 62.72, 61.10, 57.34, 52.65, 25.85, 21.22; T-IR: v ~ = 3778, 3329, 2924, 2852, 2163, 1728, 1514, 1434, 1376, 1270, 1187, 1136, 1020 cm -1 ; RMS: calcd. for [M+] + C N 2 6 = ; found: ; [ α ] RT D = -6.8 (c = 1.0 in C 2 Cl 2 ); PLC conditions: CIRALPAK IA column, (C 2 Cl 2 /Et = 100/2) / iso-hexane = 50/50, flow rate = 0.5 ml min -1, minor enantiomer: t R = min; major enantiomer: t R = min. N N (1S,3R,3aS,4aS,5R,7S,7aR,8aR)-Dimethyl 3,5-bis(4 -methoxyphenyl)-1,7-dimethyl-4,8- dioxododecahydropyrrolo[3,4-f]isoindole-1,7-dicarboxylate (4c) 1 NMR (400 Mz, CDCl 3 ): δ 7.05 (d, J = 8.7 z, 4), 6.76 (d, J = 8.7 z, 4), 4.61 (d, J = 9.0 z, 2), 3.77 (s, 12), 3.29 (d, J = 9.4 z, 2), 3.20 (dd, J = 9.4, 9.0 z, 2), 1.47 (s, 6); 13 C NMR (101 Mz, CDCl 3 ): δ , , , , , , , 69.03, 62.32, 60.75, 57.29, 55.26, 52.66, 25.84; T-IR: v ~ = 3778, 3660, 2922, 2853, 2342, 2163, 1729, 1609, 1512, 1459, 1376, 1246, 1137, 1031 cm -1 ; RMS: calcd. for [M+] + C N 2 8 = , found: ; [ α ] RT D = -8.3 (c = 1.0 in C 2 Cl 2 ); PLC conditions: CIRALPAK IA column, (C 2 Cl 2 /Et = 100/2) / iso-hexane = 50/50, flow rate = 0.5 ml min -1, minor enantiomer: t R = min; major enantiomer: t R = min. 73

74 N N (1S,3R,3aS,4aS,5R,7S,7aR,8aR)-Dimethyl dioxododecahydropyrrolo[3,4-f]isoindole-1,7-dicarboxylate (4d) 1 NMR (500 Mz, CDCl 3 ): δ (m, 4), (m, 4), 4.61 (d, J = 6.9 z, 2), 3.76 (s, 6), (m, 4), 1.54 (s, 6); 13 C NMR (126 Mz, CDCl 3 ): δ , , , (d, J = z), (d, J = 3.2 z), (d, J = 8.0 z), (d, J = 21.4 z), 69.40, 62.07, 61.75, 56.76, 52.76, 26.11; T-IR: v ~ = 3778, 3351, 2926, 2853, 2163, 1722, 1507, 1375, 1296, 1246, 1167, 1072, 1017 cm -1 ; RMS: calcd. for [M+] + C N 2 6 = , found: ; [ α ] RT D = 2.6 (c = 1.0 in C 2 Cl 2 ); PLC conditions: CIRALPAK IA column, (C 2 Cl 2 /Et = 100/2) / iso-hexane = 50/50, flow rate = 0.5 ml min -1, minor enantiomer: t R = min; major enantiomer: t R = min. N N (1S,3R,3aS,4aS,5R,7S,7aR,8aR)-Dimethyl 3,5-bis(4 -fluorophenyl)-1,7-dimethyl-4,8-3,5-bis(3 -fluorophenyl)-1,7-dimethyl-4,8- dioxododecahydropyrrolo[3,4-f]isoindole-1,7-dicarboxylate (4e) 1 NMR (500 Mz, CDCl 3 ): δ (m, 2), 6.92 (d, J = 10.1 z, 2), (m, 4), 4.61 (d, J = 7.9 z, 2), 3.75 (s, 6), 3.43 (dd, J = 9.3, 7.9 z, 2), 3.31 (d, J = 9.3 z, 2), 1.58 (s, 6); 13 C NMR (126 Mz, CDCl 3 ): δ , , , (d, J = z), (d, J = 7.2 z), (d, J = 8.7 z), (d, J = 2.5 z), (d, J = 20.9 z), (d, J = 22.4 z), 69.56, 62.42, 62.23, 56.38, 52.84, 26.27; T-IR: v ~ = 74