MULTICOMPONENT REACTIONS AND ORGANOCATALYSIS: A SUITABLE COMBINATION FOR STEREOSELECTIVE SYNTHESIS OF HIGHLY SUBSTITUTED BENZAZEPINES

Transcription

1 MULTICMPET REACTIS AD RGACATALYSIS: A SUITABLE CMBIATI FR STERESELECTIVE SYTHESIS F HIGHLY SUBSTITUTED BEZAZEPIES Martina Spallarossa Department of Chemistry and Industrial Chemistry, University of Genoa

2 Main Isocyanide based multicomponent reactions Atom economy Step economy Decoration diversity X Scaffold diversity X Stereochemical issue 2

3 Main Isocyanide based multicomponent reactions Atom economy Step economy Decoration diversity X Scaffold diversity X Stereochemical issue Use of chiral inputs rganocatalysis 3

4 The target R 4 PG-H * * * H R 2 R 3 a new family of seven-membered heterocycles 3 new contigous stereogenic centers 4 possible points of diversity Moni, L.; Basso, A.; Banfi, L.; Galatini, A.; Spallarossa, M.; Riva, R. J. rg. Chem. 2014, 79,

5 Retrosynthetic Analysis BocH * * * * * H R 2 R 4 R4 R 4 R 3 Ugi-3C BocH Staudinger aza-wittig BocH * * 3 Mannich reaction Boc H H R 4 R R Moni, L.; Basso, A.; Banfi, L.; Galatini, A.; Spallarossa, M.; Riva, R. J. rg. Chem. 2014, 79,

6 Synthesis of Boc-imine LiAlH 4, THF, 3h, rt, 98% H H S-PPL, vinyl acetate, ipr 2, 48h, 20 C 91% H 1) MsCl, TEA, DCM 2) a 3, DMF H 3) KH, MeH, 88% from TEMP, PhI(Ac) 2, DCM, 2h, rt Boc 3 Cs 2 C 3, THF, 2h, 40 C HBoc S 2 ptol 3 TolS 2 a, BocH 2, HCH, H 2, 48h, rt 50% from Qing, Z.; Takacs, J. M. rg. Lett. 2008, 10, 545. Banfi, L.; Guanti, G.; Riva, R. Tetrahedron: Asymmetry 1995, 6, Yang, J. W.; Stadler, M.; List, B Angew. Chem. Int. Ed. 2007, 46,

7 rganocatalytic Mannich Reaction Boc H H L-Pro (20%) HBoc 3 abh 4, MeH HBoc 3 CH 3 C, 48h, 0 C, 13 77% H syn:anti 97:3 ee > 99% Yang, J. W.; Pan, S. C.; List, B. rg. Synth, 2009, 86, 11. Yang, J. W.; Stadler, M.; List, B Angew. Chem. Int. Ed. 2007, 46,

8 Staudinger Aza Wittig/Ugi-Joullié HBoc PPh 3, THF, 30min, 0 C BocH Cl DCM, 18h, rt S C 2 H BocH * * * H t-buc S Cl Yield: 58% (4 steps) 3 diastereomers 64:22:14 8

9 relative order of stability (PM3 ): enamine > cis imine trans imine BocH BocH BocH R 2 H A major stereoisomer ee > 99% BocH H BocH R 2 H D 14 HBoc 3 CH Staudinger aza-wittig (SAW) BocH BocH R 2 H B H R1 R 2 C 9

10 Relative configuration of the isomers BocH H S A Cl 10

11 Relative configuration of the isomers BocH H S B Cl! 11

12 Relative configuration of the isomers BocH H S Cl C 12

13 Configuration of the two epimeric imines A careful observation of the preferred conformation of cis imine suggests that the bottom face is relatively free and therefore a high diastereoselectivity favouring the product A is expected. n the other hand, in the preferred conformation of trans imine, the upper face is encoumbered by the axial H(Boc) group, but the lower face is also encoumbered, this time by the axial methyl group. Therefore the Ugi- Joullié reaction is expected to be less diastereoselective and slower. 13

14 Study of the scope Ac H Supported PPL 19 H H Supported Amano PS H Ac regioselectivity problem enzyme catalysis 14

15 Study of the scope H RC 2 CH=CH 2 R H R H H 18a 19a: R=Me 19b: R=Pr a 21a: R=Me 21b: R=Pr R b 18b: R=Me 18c: R=Pr R entry subs products lipase solvent lipase/substrate temp time a : b yield (mg/mmol) (a + b) conv 1 18a 19a, 21a S-Amano PS vinil acetate C 2 h 37:63 77% 60% 2 18a 19a, 21a S-PPL vinil acetate C 2 h 75:25 76% 50% 3 18a 19b, 21b Amano AK vinil butyrate 22 0 C 6 h 0:100 40% 80% 4 18a 19b, 21b S-PPL vinil butyrate C 24 h 100:0 66% 67% 5 18a 19b, 21b CAL vinil butyrate C 6 h 68:32 76% 62% 6 18b 19a, 21a CAL buffer/ipr 2 d C 15 h 21:79 20% 85% 7 18c 19b, 21b CAL buffer/ipr 2 d C 19 h 12:88 25% 33%! 15

16 Study of the scope Boc H L-Pro, CH 3 C, 71% HBoc abh 4, MeH HBoc H 3 Ph Ph sin:anti 96:4 ee > 99% 3 Boc H L-Pro, CH 3 C, 68% HBoc abh 4, MeH HBoc H 3 Ph Ph sin:anti 88:12 ee > 99% 3 16

17 Library HBoc BocH R 2 S 2 -ptol Mannich reaction SAW/Ugi-Joullié 14 3 R 2 R 3 -C R 4 -C 2 H 17a-o R 4 HR 3 17a = H R 2 = Me R 3 = t -Bu R 4 = 5-Cl-2-thienyl Y (A): 53% Y (A + B + C): 83% 17b = H R 2 = Me R 3 = n -Bu R 4 = 3--C 6 H 4 Y (A): 48% Y (A + B + C): 76% 17c = H R 2 = Me R 3 = n -Bu R 4 = Ph Y (A): 60% Y (A + B + C): 86% 17d = H R 2 = Me R 3 = 2,6 -(Me 2 )-C 6 H 3 R 4 = Et Y (A): 55% Y (A + B + C): 84% 17e = H R 2 = Me R 3 = CH 2 C 2 Et R 4 = Et Y (A): 53% Y (A + B + C): 83% 17f = H R 2 = Me R 3 = cyclohexyl R 4 = S -BnCHHFmoc Y (A): 48% Y (A + B + C): 68% 17g = H R 2 = Me R 3 = nc 5 H 11 R 4 = S -iprchhcbz Y (A): 55% Y (A + B + C): 78% 17h = H R 2 = Me R 3 = Bn R 4 = MeCH 2 Y (A): 55% Y (A + B + C): 73% 17i = H R 2 = Bn R 3 = t -Bu R 4 = 5-Cl-2-thienyl Y (A): 42% Y (A + B + C): 69% 17l = H R 2 = Bn R 3 = Me R 4 = 3-Me-C 6 H 4 Y (A): 47% Y (A + B + C): 70% 17m = 8 - R 2 = Bn R 3 = CH 2 C 2 Et R 4 = Ph Y (A): 33% Y (A + B + C): 46% 17n = 8 - R 2 = Bn R 3 = Bn R 4 = CH 2 HFmoc Y (A): 47% Y (A + B + C): 57% 17o = 7 - R 2 = Bn R 3 = t -Bu R 4 = Et Y (A): 30% Y (A + B + C): 41% 17

18 Secondary transformations BocH H R 2 R 3 Suzuki reaction BocH Ph BocH Ph H PhB(H) 2, a 2 C 3, Pd(Ac) 2, PPh 3 THF, 2h, 100 C MW, 76% H 18

19 Secondary transformations BocH H R 2 R 3 Suzuki reaction BocH Ph BocH Ph H PhB(H) 2, a 2 C 3, Pd(Ac) 2, PPh 3 THF, 2h, 100 C MW, 76% H 19

20 Conclusion ew method for fast assembly of a new family of seven-membered heterocycles. Possibility of synthesizing, in high enantiomeric excess, unknown azido aldehydes by an organocatalytic procedure. Isolation in good overall yield of a single stereoisomer (out of eight) of a new heterocyclic structure endowed with three contiguous stereogenic centers. The final products can be further derivatized. 20

21 21