Efficient Kinetic Macrocyclization

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1 Efficient Kinetic Macrocyclization Wen Feng, Kazuhiro Yamato, Liuqing Yang, Joseph S. Ferguson, Lijian Zhong, Lihua Yuan,* Xiao Cheng Zeng, * and Bing Gong * College of Chemistry and Institute of uclear Science and Technology, Sichuan University, Chengdu, , Sichuan, China Department of Chemistry, University at Buffalo, The State University of ew York at Buffalo, Buffalo, ew York Department of Chemistry, University of ebraska-lincoln, Lincoln, ebraska Supporting Information S1

2 I. Competition eactions and Synthesis I-1. Competition reaction of trimeric diamine 11 with diacid chlorides 12 and 13 I-2. Competition reaction of dimeric amine 14 with diacid chlorides 15 and 16 I-3. The synthesis of trimeric precursors for forming the 16-residue 22c I-4. The synthesis of pentameric precursors for forming the 18-residue 23c II. Additional MALDI Spectra Figure S19. The MALDI spectrum of isolated 14-residue macrocycle 21c Figure S20. The MALDI spectrum of isolated 16-residue macrocycle 22c Figure S21. The MALDI spectrum of isolated 18-residue macrocycle 23c III. Additional M Spectra Figure S22. 1 M spectrum of 14-residue macrocycle 21c recorded in CDCl 3 Figure S C M spectrum of the 14-residue macrocycle 21c recorded in CDCl 3. Figure S24. 1 M spectrum of the 16-residue macrocycle 22c recorded recorded in 98%CDCl 3-2%CD 3 D. Figure S C M spectrum of the 16-residue macrocycle 22c recorded in 98%CDCl 3-2% CD 3 D. Figure S26. 1 M spectrum of the 18-residue macrocycle 23c recorded in CDCl 3. Figure S C M spectrum of the 18-residue macrocycle 23c recorded in CDCl 3 with 3% CD 3 D. IV. Ab initio Calculation V. Kinetic Simulation of Steps Leading to 14-, 16-, and 18-Macrocycles S2

3 I. Competition eactions and Synthesis I-1. Competition reaction of trimeric diamine 11 with diacid chlorides 12 and 13 Me 2 Me Me Me Me 2 11' (0.5 mm) Me Me 12' (0.5 mm) 13' (0.5 mm) Me = Me Me 2 /Pd-C 2 2 Cl Cl Me Me Me + + Me (CCl) 2 C 2 Cl 2 DMF (trace amt) Cl Me (i-c 3 7 ) 2 C 2 5 Cl Me 0 o C, C 2 Cl 2 C 3 C 3 C 3 1e C 3 C3 C 3 + other products Compounds 11 and 12 were prepared based on procedures we reported before. 1 Compound 13 was reported by us before. 1 Compound 11 was converted into 11 by catalytic hydrogenation. Compound 11 was used directly in the subsequent reaction without further purfication. Compounds 12 and 13 were mixed together and treated with oxalyl chloride. The resultant mixture containing diacid chlorides 12 and 13 was directly used for reacting with 11. Trimeric diamine 11 : 1 M (400 Mz, CDCl 3 ) δ9.88 (s, 2), 9.25 (s, 2), 8.57 (s, 1), 6.53 (s, 1), 6.21 (s, 2), 4.22 (s, 6), (m, 6), 3.67 (t, J=7.9, 2), 1.99~1.88 (m, 4), 1.63~1.54 (m, 4), 1.33~1.24 (m, 4), 1.06 (dd, 12), 0.97 (m, 12). 13 C M (100 Mz, CDCl 3 ) δ161.3, 160.7, 152.8, 150.4, 136.6, 130.9, 121.4, 117.0, 113.9, 96.9, 95.1, 74.6, 74.5, 56.7, 34.7, 34.5, 25.9, 25.8, 16.3, 16.2, 11.2, ESI-MS (m/z) calcd. for C (M + ) ; Found (M + ). Trimeric diacid 12 : 1 M (400 Mz, CDCl 3 ) δ9.72 (s, 2), 9.58 (s, 1), 8.93 (s, 2), 6.50 (s, 2), 6.45 (s, 1), 4.08 (s, 6), 3.96 (s, 6), 3.88 (m, 2 ), 3.86 (s, 6), 3.77 (m, 2), 1.94 (m, 2), 1.61 (m, 2), 1.30 (m, 2), 1.07(d, J = 6.4 z, 6), 0.99 (t, J = 7.2 z, 6). 13 C M (150Mz, 90%CDCl 3-10%CD 3 D) δ167.5, 164.2, 162.8, 162.6, 146.4, 137.1, 120.4, 115.5, 114.5, 113.0, 97.6, 96.4, 74.6, 57.2, 56.8, 35.3, 26.4, 16.7, ESI-MS (m/z) calcd. for C (M + ) ; Found (M + ). S3

4 Competition reaction. A mixture of 12 (1 equiv., 0.5 mm), 13 (1 equiv., 0.5 mm), anhydrous methylene chloride, oxalyl chloride (8 equiv.) and 1 drop DMF was stirred for 5 hrs at room temperature. The solvent and excess oxalyl chloride were then removed under reduced pressure. The resulting diacid chloride was dissolved in methylene chloride, which was then added concurrently to a pre-cooled solution of 11 (1 equiv., 0.5 mm) in C 2 Cl 2 containing diisopropylethylamine (DIEA, 7 equiv) at 0 C. The reaction mixture was stirred in an ice bath for 3 hrs and then for 8 hrs at room temperature, followed by stirring under reflux for another 1 hr. Methanol (excess) was then added to the reaction mixture. After removal of solvent, the remaining residue was triturated with C 3 and EA before being analyzed with MALDI and 1 M. ii m/z i: ii: [1e+ + ] ii : iv: [1e+a + ] v: vi: (8-residue macrocycle, [M+ + ]) i iii iv v vi Figure S1. The MALDI spectrum of the crude products from the reaction of 11, 12, and 13. a a 3 C C 3 C 3 C 3 3 C a a C 3 a Figure S2. The 1 M spectrum of the crude products from the reaction of 11, 12, and 13. S4

5 I-2. Competition reaction of dimeric amine 14 with diacid chlorides 15 and 16 (a) 3 C C 2 5 a) Cl X 15' X = C 3 15'' X = b) c) 3 C C C C 3 C 3 X X C 3 16' X = C 3 16'' X = = 14' X = 2 14 X = 2 (b) C 2 5 C 3 Cl C (4 mm) C C 3 Cl 14 (4 mm) C 3 16 (4 mm) C 3 3 C 3 C C 2 5 C 3 C 3 d) 3 C 3 C C 2 5 C C = C 3 C 3 eagents and conditions: a) (i) (CCl) 2, DMF (cat.), C 2 Cl 2, 1hrs; (ii) Et 3 Cl, DIEA, C 2 Cl 2, rt., 3 hrs; (iii) K, Et, reflux, 2 hrs; b) (i) (CCl) 2, DMF (cat.), C 2 Cl 2, 1 hr; (ii) -(5-Amino-2,4-dimethoxyphenyl)-acetamide, DIEA, C 2 Cl 2, rt., 3 hrs; (iii) K, Et, reflux, 2 hrs; c) (i) 2,4-Dimethoxy-5-nitrophenylamine, EDCI, Bt, C 2 Cl 2, r.t. 24 hrs; (ii) 2, 10% Pd/C, CCl 3 / Me, 52 C; d) (i) (CCl) 2, DMF (cat.), 0 C,C 2 Cl 2, r.t. 1 hr; (ii) DIEA, C 2 Cl 2, 0 C. 4,6-Bis-(2-ethylhexyloxy)-isophthalic acid monomethyl ester, -(5-Amino-2,4- dimethoxy-phenyl)-acetamide, 2,4-dimethoxy-5-nitro-phenylamine, and compounds were synthesized according to procedures previously reported by us. 1 Competition reaction. A mixture of acids 15 (1 equiv. 4 mm) and 16 (1 equiv., 4 mm), anhydrous methylene chloride (20 ml), oxalyl chloride (4 equiv.) and DMF (4 µl) S5

6 was stirred for 1 hour at room temperature. The solvent and excess oxalyl chloride were then removed. The resulting diacid chloride was dissolved in methylene chloride. This solution was then added to a precold solution of 14 (1 equiv, 4 mm) in C 2 Cl 2 containing DIEA (4 equiv) at 0 C. The reaction was stirred at ice bath for 3 hrs and then was quenched with C 3 CCl and C 3. The solvent and other volatile components were then removed under reduced pressure. The solid residue left was directly analyzed by 1 M using p-xylene as the internal standard, which revealed that trimer 17 formed in a yield of 37.2% and tetramer 18 was present in 32.1%. The reaction mixture was also subjected to separation by column chromatography (silica gel, CCl 3 /EtAc/C 3 =6/6/1) into fractions containing trimer 17, tetramer 18, and other impurities. Analyzing the fractions containing 17 and 18, respectively, by 1 M using p-xylene as the internal standard confirmed that the two products formed in similar yields (24.7% for 17 and 23.0% for 18). Monomer (15 ): (Monomer 15 was obtained in a yield 99.7% of from the monoester acid chloride). Compound 15 was obtained in a yield 89.0% from M (400 Mz, CDCl 3 ) δ10.36 (s, 1), 9.00 (s, 1), 7.52 (t, J=5.0,1), 6.52 (s, 1), 4.15 (m, 2), 4.08 (m, 2), 3.50 (m, 2), 1.84 (m, 2), 1.53 (m, 4), 1.47 (m, 4), 1.35 (m, 8), 1.23 (t, J=7.2, 3), 0.98 (m, 6), 0.92 (m, 6). 13 C M (100 Mz, CDCl 3 ) δ165.4, 163.7, 161.8, 161.4, 138.2, 115.7, 110.9, 96.6, 72.6, 72.0, 39.6, 39.3, 34.6, 30.8, 30.4, 29.1, 29.0, 24.1, 23.8, 22.9, 22.8, 14.8, 13.9, 11.1, ESI-MS (m/z) calcd. for C (M+ + ) ; Found (M+ + ). Figure S3. 1 M spectrum of 15 in CDCl 3. S6

7 Figure S4. 13 C M spectrum of 15 in CDCl 3. Dimer (16 ): (Compound 16 was obtained in a yield 91.4% from the monoester acid chloride). Compound 16 was obtained in a yield 97.0% from M (400Mz, CDCl 3 ) δ10.32 (s, 1), 9.42 (s, 1), 9.07 (s, 1), 8.93 (s, 1), 7.34 (s, 1), 6.55 (s, 1), 6.49 (s, 1), 4.16 (m, 2),4.12 (m, 2), 3.87 (s, 3), 3.85 (s, 3), 2.17 (s, 3), 1.95 (m, 1), 1.85 (m, 1),1.53 (m, 4), 1.46 (m, 4), 1.34 (m, 8), 0.98 (t, J=8.0, 3), 0.93 (m, 6), 0.87 (t, J=8, 3). 13 C M (100Mz, CDCl 3 ) δ168.1, 164.6, 161.6, 161.5, 161.1, 146.7, 146.5, 139.0, 120.2, 119.8, 117.2, 116.5, 110.9, 96.5, 95.0, 77.2, 72.6, 72.7, 56.0, 55.8, 39.2, 38.9, 30.4, 30.1, 29.0, 28.9, 24.4, 23.8, 23.6, 23.0, 22.9, 14.0, 11.1, ESI- MS (m/z) calcd. for C (M+ + ) ; Found (M+ + ). Figure S5. 1 M spectrum of 16 in CDCl 3. S7

8 Figure S6. 13 C M spectrum of 16 in CDCl 3. Dimer (14 ): Yield 73.2%. 1 M (400 Mz, CDCl 3 ) δ9.70 (s, 1), 9.18 (s, 1), 8.89 (s, 1), 7.60 (s, J=6.0, 1), 4.07 (m, 4), 4.02 (m, 3), 3.82 (s, 3), 3.51 (m, 2), 1.95 (m, 1), 1.82 (m, 1), 1.58~1.49 (m, 6), 1.38~1.30 (m,6), 1.26~1.22 (m,7),1.02 (t, J=6.0,3), 0.95 (m, 6), 0.87 (t, J=8.0, 3). 13 C M (100Mz, CDCl 3 ) δ164.2, 161.8, 160.4, 159.8, 153.5, 150.8, 136.9, 130.8, 121.2, 118.0, 114.6, 114.2, 96.1, 95.5, 72.8, 71.7, 56.4, 56.3, 39.6, 38.6, 34.5, 30.8, 30.0, 29.1, 28.8, 24.1, 23.4, 23.0, 23.0, 14.9, 14.0, 14.0, 11.1, ESI-MS (m/z) calcd. for C (M+ + ) ; Found (M+ + ). Figure S7. 1 M spectrum of 14 in CDCl 3. S8

9 Figure S8. 13 C M spectrum of 14 in CDCl 3. 15:24: _2ME 31 (0.530) AM (Cen,4, 80.00, Ar, ,0.00,0.70); Sm (SG, 2x3.00); Cm (7:59) Dec-2008 TF MS ES+ 8.27e3 % m/z Figure S9. ESI-MS Spectrum of 14. Trimer (17): 1 M (400 Mz, CDCl 3 ) δ9.47 (s, 2), 9.08 (s, 2), 9.03 (s, 1), 7.55 (t, J=6.0, 2), 6.50 (s, 2), 6.49 (s, 1), (m, 8), 3.85 (s, 6), 3.49(m, 4), 1.93(m, 2), 1.81(m,2), 1.56~1.45 (m, 16), 1.35~1.30 (m, 16), 1.22(t, J=8.0, 6), 0.99 (t, J=6.0, 4), 0.93 (m, 12), 0.87 (m, J=6.0,6). 13 C M (100 Mz, CDCl 3 ) δ164.3, 162.1, 160.2, 160.0, 147.0, 137.3, 120.3, 118.4, 115.6, 115.2, 96.3, 45.0, 72.3, S9

10 71.5, 55.8, 39.6, 38.9, 34.4, 30.8, 30.2, 29.1, 29.0, 24.1, 23.6, 23.0, 22.9, 14.9, 14.0, 11.2, ESI-MS (m/z) calcd. for C (M+ + ) ; Found (M+ + ). Figure S10. 1 M spectrum of 17 in CDCl 3. Figure S C M spectrum of 17 in CDCl 3. S10

11 15:32: _3ME 17 (0.291) AM (Cen,4, 80.00, Ar, ,0.00,0.70); Sm (SG, 2x3.00); Cm (7:59) Dec-2008 TF MS ES+ 1.02e % m/z Figure 12. ESI-MS Spectrum of 17 Tetramer (18): 1 M (400 Mz, CDCl 3 ) δ9.48~9.46 (m, 2), 9.07 (s, 2), 9.03 (s, 1), 8.78 (s, 1),7.56 (s, 1), 7.37 (s, 1), 6.56 (s, 1), 6.51 (s, 2), 6.44 (s, 1), (m, 8), 3.86 (s, 6), 3.82 (s, 6), 3.48 (m, 2),2.14 (s, 3), 1.94~1.80(m, 4), 1.56~1.44 (m, 16), 1.35~1.26 (m,16), 1.21 (t, J=6.0, 3), 1.00~0.85 (m, 24). 13 C M (100Mz, CDCl 3 ) δ164.3, 162.2, 162.1, 162.0, 161.9, 160.3, 160.0, 146.9, 137.5, 137.1, 120.4, 120.1, 119.0, 118.0, 115.6, 115.4, 115.0, 96.6, 96.4, 94.9, 72.4, 71.6, 55.8, 39.6, 39.0, 38.9, 38.8, 34.4, 30.8, 30.2, 29.1, 28.9, 24.1, 23.6, 23.0, 22.9, 14.9, 14.0,13.9, 11.2, ESI-MS (m/z) calcd. for C (M+ + ) ; found (M+ + ). Figure S13. 1 M spectrum of 18 in CDCl 3. S11

12 Figure S C M spectrum of 18 in CDCl 3. 15:41: _4ME 39 (0.667) AM (Cen,4, 80.00, Ar, ,0.00,0.70); Sm (SG, 2x3.00); Cm (8:59) Dec-2008 TF MS ES+ 4.14e3 % m/z Figure S15. ESI-MS Spectrum of 18. S12

13 Figure S16. The 1 M spectrum (in CDCl 3 ) of the product mixture of the competition reaction of 14, 15, and 16. Peaks corresponding to the two products are labeled with two colored symbols. Figure S17. The 1 M spectrum (in CDCl 3 ) of the fraction containing 17 separated from the mixture of the competition reaction of 14, 15, and 16 by chromatograpy (silica gel, CCl 3 /EtAc/C 3 = 6/6/1). S13

14 Figure S18. The 1 M spectrum (in CDCl 3 ) of the fraction containing 18 separated from the mixture of the competition reaction of 14, 15, and 16 by chromatograpy (silica gel, CCl 3 /EtAc/C 3 = 6/6/1). S14

15 I-3. Synthesis of trimeric precursors for the exclusive formation of the 16-residue 22c ClC CCl + polysulfide, water, 90 o C '' Et ' C 2Cl ' 2, Pd/C, 4 Pa, 48 0 C ClC 2 CCl = 22c 2, 4-Bis-[(S)-2-methylbutoxy)]-5-nitro-aniline (20 ). A polysulfide solution was prepared by heating a mixture of sodium hydrosulfide hydrate (11.1 g, as x 2 ), sulfur (1.80 g, 56.2 mmol) and sodium hydroxide (3.3 g, 83.3 mmol) in 140 ml of water first at 80 o C for 10 min and then being allowed to cool down to room temperature. The resulting clear, faintorange solution was added dropwise in two batches (90 ml in 2.5h and 50 ml in the next 4 h) at 90 o C to a flask containing 1,5-bis-(2-methyl-butoxy)-2,4-dinitro-benzene (10.0 g, 29.4 mmol). The reaction mixture was allowed to cool down to room temperature and to stand overnight. The brown solution after removal of the solvent was subjected to chromatography (n-hexanes/etac, 50:1) to provide the product as a brown oil (7.1g, 78%). 1 M (500 Mz, CDCl 3 ) δ7.39 (s, 1), 6.44 (s, 1), 3.93~3.70 (m, 4), 3.70 (s, 2), 1.94 (m, 2), 1.59 (m, 2), 1.32 (m, 2), 1.06 (d, d, 6), 1.01~0.94 (m, 6). 13 C M (75.5 Mz, CDCl3) 152.1, 148.3, 132.1, 129.9, 111.2, 99.1, 75.5, 73.7, 35.0, 34.7, 26.2, 26.0, 16.6, 16.5, 11.4; MS (ESI) m/z, Calcd for C (M + ), found (M+ + ). Trimer (25 ). This compound was prepared by coupling acid chloride 19 with compound 20 based on the same procedures we reported before. 1,2 Yield: 88.2%. 1 M (500 Mz, CDCl 3 ) δ10.37 (s, 2), 9.28 (s, 2), 8.08 (s, 2), 6.55 (s, 2), 4.03 (s, 6), 3.98~3.92 (m, S15

16 4), 3.91~3.86(m, 4), 2.09~1.95(m, 2), 1.78~1.61(m, 2), 1.46~1.20 (m, 4), 1.21~1.15(m, 4), 1.06~0.98(m, 12), 0.98~0.89 (m, 12); 13 C M (75.5 Mz, CDCl 3 ) δ161.95, , , , , , , , , 97.82, 74.38, 73.97, 61.97, 34.86, 26.71, 26.59, 16.53, 16.39, 10.97; MS (ESI) m/z, Calcd for C (M + ), found (M+ + ). Trimer (25). A solution of the trimer diamine was prepared from dinitro trimer 25 (377 mg, 0.33 mmol) by catalytic hydrogenation in CCl 3 /Me (80 ml). The generated oligomer 25 was reacted directly with acid chloride 19 in C 2 Cl 2 for forming macrocycle 22c without further purification. S16

17 I-4. Synthesis of pentameric precursors for the exclusive formation of the 18-residue 23c ' C (1) 2, Pd-C, 2 Pa (1) K, C 3 (2) (2) Cl ClC CC 3 3 C 2 C C 2 C ' (1) (CCl) 2 (2) Et 3 C '' 26' 2 2 2, Pd/C, 4 Pa, 50 o C ClC CCl Et 3 19 = 23c S17

18 Trimer diester 27. Compound 20 (337 mg, 0.99 mmol) was hydrogenated in the presence of 15% Pd on carbon (50 mg) at 2 Pa for 4 hr at room temperature. The solution was filtered in darkness as fast as possible followed by immediate removal of the solvent. The reduced diamine was used for the immediate coupling reaction. Acid chloride 19, prepared from 2,3- dimethoxy-terephthalic acid monomethyl ester (500 mg, 2.08 mmol), was dissolved in methylene chloride (30 ml) and added dropwise to a mixture of the above diamine and triethyl amine (526 mg, 5.2 mmol). The solution was stirred at room temperature under argon overnight. The solvent was removed and the residue was extracted with ethyl acetate and water. After removing ethyl acetate the crude product was subjected to chromatography (CCl 3 /EtAc, 60:1) to afford 27 as a yellow solid (650 mg, 90.6%). 1 M (500 Mz, CDCl 3 ) δ10.32 (s, 2), 9.76 (s, 1), 8.07 (d, J = 8.0 z, 2), 7.62 (d, J =8.0 z, 2), 6.55 (s, 1), 4.02 (s, 6), 3.98 (s, 6), 3.94 (s, 6), 3.86 (m, 4), 2.01 (m, 2), 1.69 (m, 2), 1.32 (m, 2), 1.10 (d, J = 6.5 z, 6), 0.99 (t, J = 7.5 z, 6); 13 C M (75.5Mz, CDCl3) 165.8, 161.1, 153.3, 152.3, 145.3, 131.2, 128.9, 126.5, 126.0, 120.9, 114.7, 96.8, 74.0, 61.9, 61.8, 52.4, 35.0, 26.1, 16.4, 11.4; MS (ESI) m/z, Calcd for C (M + ), found (M+ + ), (M+a + ). Trimer diacid 28. A mixture of compound 27 (650 mg, 0.90 mmol) in Me, potassium hydroxide (0.26 g, 4.68 mmol) in water (1.0 ml) was refluxed for 3 hr. The reaction mixture was acidified followed by removing most of the solvent, and the residue was extracted twice with ethyl acetate. The organic layer was washed with water, dried over anhydrous a 2 S 4 and evaporated to afford the desired product as a yellow solid (605 mg, 96.5%). 1 M (300 Mz, CDCl 3 ) δ10.18 (s, 2), 9.74 (s, 1), 8.14 (d, J = 8.4 z, 2), 7.96 (d, J = 8.7 z, 2), 6.57 (s, 1), 4.14 (s, 6), 4.03 (s, 6), 3.92 (m, 2), 3.87 (m, 2), 1.99 (m, 2), 1.69 (m, 2), 1.35 (m, 2), 1.11 (d, J = 6.3 z, 6), 1.00 (t, J = 7.2 z, 6); 13 C M (75.5 Mz, CDCl 3 ) δ165.5, 160.7, 152.7, 151.2, 145.5, 132.8, 127.7, 127.4, 125.7, 120.6, 114.7, 96.6, 73.9, 62.4, 62.2, 35.0, 26.1, 16.5, 11.4; MS (ESI) m/z, Calcd for C (M + ), found (M+ + ), (M+a + ). Pentamer 26. Diacid 27 was converted into its corresponding acid chloride form by treating with (CCl) 2 in C 2 Cl 2 with ~1 drop of DMF at room temperature. The resulted acid chloride was then coupled to amine 20 in the presence of Et 3, leading to pentamer 26 in 65.0% yield. 1 M (400 Mz, CDCl 3 ) δ10.38 (s, 2), (s, 2), 9.68 (s, 1), 9.33 (s, 2), 8.13 (d, J = 8.4 z, 2), 8.05 (d, J = 8.4 z, 2), 6.58 (s, 1), 6.54 (s, 2), 4.06 (s, 6), 4.04 (s, 6), 4.02(m, 4), 3.95 (m, 4), 3.88 (m, 4), 1.97 (m, 6), 1.71 (m, 4), 1.62 (m, 2), 1.36 (m, 6), 1.15 (d, J = 6.4 z, 6), 1.11 (d, J = 6.4 z, 6), 1.07 (d, J = 6.8 z, 6), 1.05 ~ 0.95 (m, 18); 13 C M (75.5 Mz, CDCl 3 ) δ161.6, 160.9, 152.7, 151.5, 151.4, 150.9, 145.4, 132.2, 131.3, 129.5, 127.1, 126.7, 121.0, 120.8, 118.0, 114.6, 97.6, 96.8, 74.9, 74.3, 74.0, 62.0, 61.9, 35.0, 34.9, 34.8, 26.1, 26.0, 25.9, 16.4, 16.3, 11.4, 11.3; MS (ESI) m/z, Calcd for C (M + ), found (M+ + ), (M+a + ). Pentamer diamine (26). Pentamer 26 was obtained from pentamer 26 (250 mg, 0.20 mmol) by catalytic hydrogenation (40 mg, 15% Pd on carbon) in CCl 3 /Me (40 ml) at 50 o C for 7 hr. Without further purification, diamine 26 was treated with acid chloride 19 in C 2 Cl 2 (30 ml) in the presence of triethylamine, leading to the formation of macrocycle 23c. S18

19 eferences: 1. Yuan, L..; Sanford, A..; Feng, W.; Zhang, A. M.; Ferguson, J. S.; Yamato, K.; Zhu, J.; Zeng.. Q.; Gong, B. J. rg. Chem. 2005, 70, Gong, B.; Zeng,. Q.; Zhu, J.; Yuan, L..; an, Y..; Cheng, S. Z.; Furukawa, M.; Parra,. D.; Kovalevsky, A. Y.; Mills, J. L.; Skrzypczak-Jankun, E.; Martinovic, S.; Smith,. D.; Zheng, C.; Szyperski, T.; Zeng, X. C. Proc. atl. Acad. Sci. USA 2002, 99, S19

20 II. Additional MALDI Spectra M M Figure S19. The MALDI spectrum of isolated 14-residue macrocycle 21c. M M Figure S20. The MALDI spectrum of isolated 16-residue macrocycle 22c. M M Figure S21. The MALDI spectrum of isolated 18-residue macrocycle 23c. S20

21 III. M Spectra Figure S22. 1 M spectrum of the 14-residue macrocycle 21c recorded in CDCl 3. S21

22 Figure S C M spectrum of the 14-residue macrocycle 21c recorded in CDCl 3. S22

23 Figure S24. 1 M spectrum of the 16-residue macrocycle 22c recorded in 98%CDCl 3-2%CD 3 D. S23

24 Figure S C M spectrum of the 16-residue macrocycle 22c recorded in 98%CDCl 3-2%CD 3 D. S24

25 Figure S26. 1 M spectrum of the 18-residue macrocycle 23c recorded in CDCl 3. S25

26 Figure S C M spectrum of the 18-residue macrocycle 23c recorded in CDCl 3 with 3% CD 3 D (75 Mz, room temperature). S26

27 IV. Ab Initio Calculation The ab initio density-functional calculation was carried out using the Gaussian 03 package. 1 The geometry of was optimized by using the B3LYP/6-31G(d) level of theory and basis set. Density-functional calculation shows that 21 is a non-planar ring with a shallow bowl shape, whereas 22 is a planar ring and 23 is slightly twisted with a small out-of-plane angle. eference 1 Gaussian 03, evision C.02, Frisch, M. J.; Trucks, G. W.; Schlegel,. B.; Scuseria, G. E.; obb, M. A.; Cheeseman, J..; Montgomery, Jr., J. A.; Vreven, T.; Kudin, K..; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; ega,.; Petersson, G. A.; akatsuji,.; ada, M.; Ehara, M.; Toyota, K.; Fukuda,.; asegawa, J.; Ishida, M.; akajima, T.; onda, Y.; Kitao,.; akai,.; Klene, M.; Li, X.; Knox, J. E.; ratchian,. P.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts,.; Stratmann,. E.; Yazyev,.; Austin, A. J.; Cammi,.; Pomelli, C.; chterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas,.; Malick, D. K.; abuck, A. D.; aghavachari, K.; Foresman, J. B.; rtiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin,. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; anayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; and Pople, J. A.; Gaussian, Inc., Wallingford CT, S27

V. Kinetic Simulation of Steps Leading to the 14-, 16- and 18-Macrocycles Kinetic simulation was performed using the shareware Kintecus 1 based on a typical polycondensation reaction involving two

28 V. Kinetic Simulation of Steps Leading to the 14-, 16- and 18-Macrocycles Kinetic simulation was performed using the shareware Kintecus 1 based on a typical polycondensation reaction involving two bifunctional monomers, A and B, that react with each other. All the reactive species, i.e., monomers and oligomers, are assumed to have the same reactivity. The intramolecular cyclization steps were assumed to have rates of infinitely large values. Yield Cyclic 14mer (Cy-A7B7) 16.0% Cyclic 16mer (Cy-A8B8) 15.4% Cyclic 18mer (Cy-A9B9) 13.9% Linear 20mer (A10B10) 12.2% 1. Ianni, J. C. Kintecus, version 3.95, 2008, S28

29 Complete references 14 and 17: 14. Gong, B.; Zeng,. Q.; Zhu, J.; Yuan, L..; an, Y..; Cheng, S. Z.; Furukawa, M.; Parra,. D.; Kovalevsky, A. Y.; Mills, J. L.; Skrzypczak-Jankun, E.; Martinovic, S.; Smith,. D.; Zheng, C.; Szyperski, T.; Zeng, X. C. Proc. atl. Acad. Sci. USA 2002, 99, Gaussian 03, evision C.02, Frisch, M. J.; Trucks, G. W.; Schlegel,. B.; Scuseria, G. E.; obb, M. A.; Cheeseman, J..; Montgomery, Jr., J. A.; Vreven, T.; Kudin, K..; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; ega,.; Petersson, G. A.; akatsuji,.; ada, M.; Ehara, M.; Toyota, K.; Fukuda,.; asegawa, J.; Ishida, M.; akajima, T.; onda, Y.; Kitao,.; akai,.; Klene, M.; Li, X.; Knox, J. E.; ratchian,. P.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts,.; Stratmann,. E.; Yazyev,.; Austin, A. J.; Cammi,.; Pomelli, C.; chterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas,.; Malick, D. K.; abuck, A. D.; aghavachari, K.; Foresman, J. B.; rtiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin,. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; anayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; and Pople, J. A.; Gaussian, Inc., Wallingford CT, S29

Ph 2 P(BH 3 )Li: from ditopicity to dual reactivity

S1 Supplementary Information to: Ph 2 P(BH 3 )Li: from ditopicity to dual reactivity Gabriella Barozzino Consiglio, a,b Pierre Queval, c Anne Harrison-Marchand, a Alessandro Mordini, b Jean-François Lohier,