Recent Advances in Asymmetric Synthesis of Pyrrolidine-Based Organocatalysts and Their Application: A 15-Year Update

Abstract

In 1971, chemists from Hoffmann-La Roche and Schering AG independently discovered a new asymmetric intramolecular aldol reaction catalyzed by the natural amino acid proline, a transformation now known as the Hajos-Parrish-Eder-Sauer-Wiechert reaction. These remarkable results remained forgotten until List and Barbas reported in 2000 that L-proline was also able to catalyze intermolecular aldol reactions with non-negligible enantioselectivities. In the same year, MacMillan reported on asymmetric Diels-Alder cycloadditions which were efficiently catalyzed by imidazolidinones deriving from natural amino acids. These two seminal reports marked the birth of modern asymmetric organocatalysis. A further important breakthrough in this field happened in 2005, when Jørgensen and Hayashi independently proposed the use of diarylprolinol silyl ethers for the asymmetric functionalization of aldehydes. During the last 20 years, asymmetric organocatalysis has emerged as a very powerful tool for the facile construction of complex molecular architectures. Along the way, a deeper knowledge of organocatalytic reaction mechanisms has been acquired, allowing for the fine-tuning of the structures of privileged catalysts or proposing completely new molecular entities that are able to efficiently catalyze these transformations. This review highlights the most recent advances in the asymmetric synthesis of organocatalysts deriving from or related to proline, starting from 2008.

Keywords: asymmetric organocatalysis; proline; substituted pyrrolidines; synthetic methods.

Figure 1

(a) Structures of the progenitors and most-commonly used organocatalysts; (b)–(e) the fundamental stereoselective activation mode of pyrrolidine-based organocatalysts.

Scheme 1

Use of the ester-containing proline aryl sulfonamide 1 in the conjugate addition of disubstituited aldehydes to acyclic ketones.

Figure 2

Fully substituted prolinamide organocatalysts 2 and 3 and the proposed transition state for the Michael addition of aldehydes to nitrostyrenes.

Scheme 2

(a) Synthesis of 4-hydroxyprolinamides 4a,b and 5a,b. Reagents and conditions: (a) (i) LiHMDS, THF, −20 °C; 1.5 h; (ii) CH₃I, THF, 18 h, −20 °C to rt; I-1a: 48%, I-1b: 26%; (b) NaOH in MeOH/H₂O (1:1), reflux, 5 h; I-2: 48%, I-4′: 76%, (c) for I-3a and I-5a: (S)-1-Phenylethylamine, HATU, DIPEA, DMF, rt, 4 h; I-3a: 42%, I-5a: 50%; for I-3b and I-5b: (S)-N,α-dimethylbenzylamine HATU, DIPEA, DMF, rt, 4 h; I-3b: 33%, I-5b: 31%; (d) TBAF (1M), THF, 0° C, 5 h; I-3a’: 92%, I-3b’: 98%, I-4: quantitative (e) 50% TFA/DCM, rt, 16 h., 4a: 28%, 4b: 23%, 4c: 27%, 4d: 24%. (b) Other hydroxyprolinamide catalysts obtained by Kelleher and co-workers.

Figure 3

Prolinamide organocatalysts 7a,b and the proposed transition state for the organocatalytic Michael addition of aldehydes to nitrostyrene.

Scheme 3

Synthesis of trifluoromethanesulfonamide-substituted prolinamides 8a–d. Reagents and conditions: (a) NHBn₂, NaBH(OAc)₃, 1,2-DCE, rt, 16 h; (b) (i) H₂ (1 atm), Pd/C, MeOH, rt, 24 h; (ii) Tf₂O, Et₃N, DMAP, DCM, 0 °C to rt, 1 h; (c) TFA, DCM, 0 °C to rt, 6 h; (d) EDC HCl, HOBt, DIPEA, DCM, 0 °C to rt.

Figure 4

Prolinamides 9a–d.

Figure 5

Bifunctional prolinamide catalysts 10a,b and the corresponding transition states.

Scheme 4

(a) Synthesis of prolinamides organocatalyst 11, 12, and 13a,b. Reagents and conditions: (a) ClCO₂Et, Et₃N, DCM, 0 °C to rt; (b) (i) Camphorsulfonyl chloride, Et₃N, DCM, 0 °C. 1 h; (ii) TFA, DCM, 0 °C, 1 h, 65%; (c) (i) Ketopinic chloride, Et₃N, DCM, 0 °C. 1 h; (ii) TFA, DCM, 0 °C, 1 h, 65%; (d) For 13a: (i) thiocyanatobenzene, DCM, 0 °C to rt; (ii) TFA, DCM, 0 °C, 1 h, 60%; For 13b: (i) 1-thiocyanato-3,5-bis(trifluoromethyl)benzene, DCM, 0 °C to rt; (ii) TFA, DCM, 0 °C, 1 h, 64%. (b) Synthesis of prolinamides organocatalyst 14a–c. Reagents and conditions: (e) (i) SOCl₂, reflux; (ii) NH₄SCN_, acetone; (iii) o-phenylenediamine; (f) For 14a: N-Boc-L-Proline, ethylchloroformiate; for 14b,c: N-Boc-4-hydroxy-L-Proline, ethylchloroformiate; (g) Only for 14c: TBDPSCl, DMAP, DCM; (h) TFA, DCM. (c) Synthesis of prolinamides organocatalyst 15a,b. Reagents and conditions: (i) (i) RCH₂Br, NaH, THF, 0 °C; (ii) TFA, DCM; 15a: 61%, 15b: 45%.

Figure 6

Series of prolinamide-based organocatalysts characterized by different carbocyclic rings or variably substituted aromatics.

Scheme 5

(a) Synthesis of prolinamide-organocatalysts 7b,c, 18a-h, 20 applied in the organocatalytic Biginelli reaction. (b) Synthesis of prolinamide-organocatalysts 18i,j applied in the same Biginelli reaction.

Figure 7

Bifunctional prolinamide-based organocatalysts 21a–d.

Scheme 6

Series of prolinamide-organocatalysts employed in the reaction of isatin with acetone (Py = pyridine, Qn = quinoline).

Scheme 7

Series of prolinamide-organocatalysts employed in the enantioselective cross-aldol reaction between acetone and trihalomethyl ketones or imines.

Scheme 8

(a) Synthesis of organocatalysts 25a–d. Reagents and conditions: (a) LiAlH₄, THF, 0 °C to rt, 81–98%; (b) (i) NaH, THF, rt; (ii) TBDMSCl, 85–89%; (c) TsCl, pyr, DMAP, 0 °C to rt, 80–85%; (d) NaN₃, DMF, 70 °C, 99%; (e) H₂ (50 psi), Pd/C, AcOEt/EtOH, 88–90%; (f) L-Pro-Cbz, HOBt, EDC, Et₃N, DCM, 0 °C to r.t, 88–90%; (g) TBAF, THF, rt, 85–97%; (h) H₂ (50 psi), Pd/C, MeOH, 25a: 91%, 25b: 87% , 25c:97%, 25d: 87%;(i) BAIB/Tempo, DCM/H₂O, 84–97%. (b) Synthesis of organocatalysts 25e. Reagents and conditions: (a) (i) LDA, THF, −78 °C; (ii) MeOH, 98%; (b) Ti(OiPr)₄, iPrOH, 10 °C, 10 days, 82%; (c) LiAlH₄, THF, 70 °C 96%; (d) (i) NaH, THF, rt; (ii) TBDMSCl, 60%; (e) NH₃, DIAD, PPh₃, THF, 0 °C, 84%; (f) H₂ (50 psi), Pd/C, AcOEt/EtOH, 99%; (g) L-Pro-Cbz, HOBt, EDC, Et₃N, DCM, 0 °C to r.t, 81%; (g) TBAF, THF, rt, 98%; (h) H₂ (50 psi), Pd/C, MeOH, 99%. (c) Synthesis of organocatalysts 25f. Reagents and conditions: (a) (i) LDA, THF, 97%; (b) TsCl, pyr, DMAP, 0 °C to rt, 95%; (c) NaN₃, DMF, 70 °C, 93%; (d) H₂ (50 psi), Pd/C, AcOEt/EtOH, 99%; (e) L-Pro-Cbz, HOBt, EDC, Et₃N, DCM, 0 °C to r.t, 93%; (f) H₂ (50 psi), Pd/C, MeOH, 99%. (d) Synthesis of organocatalysts 26g. Reagents and conditions: (c) TsCl, pyr, DMAP, 0 °C to rt, 87%; (d) NaN₃, DMF, 70 °C, 90%; (e) H₂ (50 psi), Pd/C, AcOEt/EtOH, 99%; (f) L-Pro-Cbz, HOBt, EDC, Et₃N, DCM, 0 °C to r.t, 83%; (h) H₂ (50 psi), Pd/C, MeOH, 99%.

Figure 8

N-prolyl sulfinamide-catalysts 27a–d containing two stereogenic centers.

Figure 9

Phthalimido-prolinamide catalyst 28 and its transition state in the enantioselective direct aldol reaction of aromatic aldehydes with ketones.

Figure 10

AZT-Prolinamides 29a,b employed in the enantioselective direct aldol reaction.

Figure 11

Intermolecular hydrogen bonding network in the transition state involving catalysts 6c,d.

Figure 12

Homochiral L-prolinamido-sulfonamides 30a–h and their calculated transition state for the asymmetric aldol reaction between acetone and aromatic aldehydes.

Figure 13

Peptides 31b–g structurally related to organocatalyst 31a.

Figure 14

Tripeptides 32a–f employed to catalyze the asymmetric aldol reaction.

Scheme 9

Tripeptide 33 employed in the asymmetric aldol reaction between acetone and α-ketoesters or α-keto amides.

Scheme 10

Synthesis of dipeptide organocatalyst 34. Reagents and conditions: (a) CbzCl, NaOH, 0 °C, 2 h, 93%; (b) O-Bn-L-threonine, EDC, HOBt, DCM:DMF (4:1), rt, 14 h, 92%; (c) TBSCl, imidazole, DCM:DMF (10:1), rt, 24 h, 78%; (d) Pd(OH)₂/C, H₂ (1 atm), rt, 12 h, 74%.

Figure 15

Prolinamide catalysts 35a–c, resembling dipeptides.

Figure 16

Series of dipeptide-like organocatalysts 36a–h, employed in the asymmetric aldol reaction in brine.

Figure 17

Proline-based α,β-dipeptides 37a–c.

Figure 18

Proline-based dipeptides 38a–e as organocatalysts for the asymmetric aldol reaction both in organic and aqueous media.

Figure 19

Hybrids dipeptide-2-pyrrolidone organocatalysts 39a–f.

Figure 20

(a) Pseudotripeptide catalysts 40a–m, characterized by the anthranilamide moiety. (b) Binding pocket characteristic of this type of catalysts. (c) Intramolecular hydrogen bonding.

Scheme 11

Tripeptide-like catalyst 41 employed for asymmetric aldol reaction between ketones and perfluoroalkyl ketones.

Figure 21

Proline-based di- and tri-peptides 42a–d employed in the asymmetric Michael reaction between ketones and nitroolefins “on water.”

Figure 22

Tripeptide H-D-Pro-Pro-Glu-NH₂ 43a.

Figure 23

(a) Amide bond conformations of H-Pro-Pro-Xaa-NH₂-type peptide organocatalysts. (b) Examples of the studied catalysts.

Scheme 12

(a) Conjugate addition reaction of aldehydes to α,β-disubstituted nitroolefins. (b) General structure of the evaluated organocatalysts (43c).

Scheme 13

Asymmetric conjugate addition of aldehydes to β,β-disubstituted nitroalkenes.

Figure 24

Series of bifunctional L-prolinamides organocatalysts 44a–d resembling dipeptides.

Scheme 14

(a) Synthesis of bifunctional tripeptides carrying phosphonic acid. Reagents and conditions: (a) Boc₂O, Na₂CO₃, NaHCO₃ (satd), rt, 24 h, >99%; (b) (i) DEAD, Ph₃P, THF, −78 °C; (ii) 2-((tert-butoxycarbonyl)amino)-3-hydroxypropanoic acid, THF, −78 °C to rt 2.5 h; (c) P(OMe)₃, 70 °C, 24 h, 53% over two steps; (d) TFA, DCM, rt, 4 h, 74%; (e) LDA, tetraethyl methylenebis(phosphonate), −78 °C, 1 h, rt, 3 h, 98%, Z/E 60/40; (f) H₂ (1 atm), Pd/C, EtOH, rt, 2 h; (g) PTSA, MeOH, rt, 6 h, 85% over two steps; (h) BAIB, TEMPO, NaHCO₃, 0 °C, 2 h, 90%; (i) TFA, rt, 4 h; (j) AcCl, MeOH, reflux, 2 h, >99% over two steps; (k) EDC∙HCl, HOBt, Et₃N, DCM, 0 °C, 30 min, rt, 12 h, 40–60%; (l) (i) TMSBr, CH₃CN, −10 °C to rt, 4 h; (ii) MeOH, 1 h, rt; (iii) NaOH; H₂O then lyophilization, 95%. (b) Key functional groups of these tripeptides. (c) Series of synthesized phosphonic acid-containing tripeptides 45a–h.

Figure 25

Series of new hybrid dipeptide-like organocatalysts 46a–m.

Scheme 15

(a) Anti-selective conjugate addition between aldehydes and nitroolefins promoted by organocatalyst 43e (Curtin–Hammett scenario). (b) Best-performing catalyst, 43e.

Scheme 16

(a) Synthesis of the tricyclic chiral catalyst 47a. Reagents and conditions: (a) DCC, BnOH, DCM, 0 °C to rt, 2 h, 98%; (b) TFA, 32 h, rt, 88%; (c) ethylchloroformate, Na₂CO₃, 0 °C to rt, 12 h, 86%; (d) H₂ (1 atm), Pd/C, MeOH, rt, 12 h, 100%. (b) Calculated transition state. (c) Other tricyclic chiral catalyst 47b,c.

Scheme 17

(a) Synthesis of the cis-ion-tagged organocatalyst 48a. Reagents and conditions: (a) 2-chloroacetyl chloride, DCM, −20 °C, 3 h, 86%; (b) N-Me-Imidazole, MeCN, 16 h, 50 °C, 65%; (c) LiNTf₂, DCM, rt, 12 h, 92%.; (d) H₂ (1 atm), Pd/C, MeOH, rt,12 h, 96%. (b) Ion-tagged cis-ester 48b. (c) Calculated transition state for catalyst 48a.

Scheme 18

Synthesis of organocatalyst 49. Reagents and conditions: (a) oxalyl chloride, DMF, benzene, rt, 12 h, 95%, (b) 4-hydroxy-L-proline, TFA, CF₃SO₃H_, rt, 3 h, 87%, (c) Et₃N, EtOAc, rt, 90%.

Scheme 19

Synthesis of pyridinium-pyrrolidines 50a–d. Reagents and conditions: (a) Zincke salt, nBuOH, reflux, 35 h, 82%; (b) (i) 4 M HCl/dioxane, rt, 5 h; (ii) solid NaHCO₃, 98%; (c) 50b: AgBF₄, CH₃CN, 92%; 50c: KPF₆, H₂O, 1 h, 94%; 50d: LiNTf₂, H₂O, 1 h, 98%.

Scheme 20

Synthesis of thio-pyrrolidines 51a–c. Reagents and conditions: (a) NaBH₄, I₂, THF, rt, 5 h, reflux, 20 h, 88%; (b) (i) 20% HBr/H₂O; (ii) EtOH, PBr₃, reflux, 10 min, 86%; (c) substituted mercapto-imidazole, CH₃CN, 80 °C, 8 h, yields not reported.

Scheme 21

Synthesis of ionic liquid anchored triazole-pyrrolidines 52a–c. Reagents and conditions: (a) BH₃∙SMe₂, THF, 0 °C, 5 h, rt, overnight, 95%; (b) TsCl, pyridine, rt, 6 h, 84%; (c) NaN₃, DMSO, 64 °C, 19 h, 90%; (d) propargyl chloride, toluene, reflux, 8 h, >99% [91]; (e) CuI, DIPEA, EtOH, reflux, 24 h; (f) 5 M HCl, EtOH, 52a: 73%; (g) 52b: NaBF₄, CH₃CN/acetone (4:1), rt, 2 days, 95%; 52c: KPF₆, CH₃CN/acetone (4:1), rt, 2 days, 92%.

Scheme 22

Synthesis of ionic liquid anchored sulfonamido-pyrrolidines 53a,b. Reagents and conditions: (a) chlorosulfonyl chloride, Et₃N, DCM, 0 °C to rt, 17 h, a: 72%, b: 98%; (b) a: (i) NaI, acetone, rt, 24 h, 96%; (ii) 1-methyl-imidazole, CH₃CN, 65 °C, 14 h, 90%; b: 1-methyl-imidazole, toluene, reflux, 3 days, 75%; (c) (i) TFA/DCM (1:1), rt, 2 h; (ii) NaHCO₃, LiNTf₂, 1 h, rt, 55a: 88%, 53b: 90% over two steps.

Scheme 23

Synthesis of ionic liquid anchored sulfonamido-pyrrolidine 54. Reagents and conditions: (a) 1-methyl-2sufonylchlorideimidazole, Et₃N, DCM, 0 °C to rt, 1 h, 96%; (b) Me₃OBF₄, AcOEt, 0 °C to rt, 2 h, 90%; (c) 4 M HCl/dioxane, rt, 5 h, 95%.

Scheme 24

Synthesis of bifunctional pyrrolidines 55a,b. Reagents and conditions: (a) benzyl (2-aminoethyl)carbamate (n = 1, HCl salt) or benzyl (3-aminopropyl)carbamate (n = 2, TFA salt), EDC, HOBt, iPr₂NEt, DMF/THF, 0 °C to rt, 17 h, 79% (n = 1), 71% (n = 2); (b) BH₃∙THF, THF, 0 °C to rt, 7 days, 69% (n = 1), 60% (n = 2); (c) Pd/C (10 mol%), H₂ (1 atm), MeOH, rt, 5 h, 98%; (d) PhNCS, CHCl₃, MeOH, aq NaHCO₃, rt, 3 h, 68% (n = 1), 47% (n = 2); (e) 10% v/v TFA/DCM, rt, then aq K₂CO₃, rt, 30 min 88% (n = 1), >99% (n = 2).

Scheme 25

Synthesis of phosphine oxide substituted pyrrolidine 56. Reagents and conditions: (a) TsCl, pyridine, 0 °C, 4 h, 92%; (b) (i) Na, ClPPh₂, dioxane, reflux, 15 h; (ii) (S)-N-tButoxycarbonylprolinol p-toluenesulfonate, rt, 19 h, 93%; (c) 30% H₂O₂, DCM, rt, 30 min; (d) TFA, DCM, rt, 12 h, 92% over two steps.

Scheme 26

Synthesis of pyrrolidinyl–camphor catalysts 57a,b. Reagents and conditions: (a) BH₃∙THF, 0 °C, 1 h, 96%; (b) pyridine, DCM, 40 °C, TsCl (syringe pump, 10 h), 8 h, 69%; (c) PCl₅, 0 °C to rt, 1 h, 96%; (d) Ph₃P, H₂O/dioxane (1:4), reflux, 1 h, 82%; (e) NaH, THF, rt, 2 h, 88%; (f) NaBH₄, DCM/MeOH (1:1), rt, 2 h; (g) TFA, DCM, rt, 1–3 h, 57a: 60%, 57b: 82% over two steps.

Scheme 27

Synthesis of pyrrolidinyl–camphor catalyst 58. Reagents and conditions: (a) PCl₅, 0 °C to rt, 1 h, 96%; (b) Na₂CO₃, KMnO₄, H₂O, heat, 1 h, 40%; (c) (i) ethyl chloroformate, Et₃N, acetone/H₂O, NaN₃, 0 °C to rt; (ii) 0.08 N HCl, 80 °C, 75%; (d) DIBAL-H, toluene, −78 °C, 2 h, 90%; (e) Ti(iPrO)₄, THF, rt, 12 h; (f) NaBH₄, EtOH, rt, 12 h, 52% over two steps; (g) TFA, DCM, rt, 19 h, 79%.

Scheme 28

Synthesis of pyrrolidine-pyridine-based catalysts 59a–d. Reagents and conditions: (a) (i) NaH, THF, 0 °C to rt, 12 h; (ii) 2-bromopyridine, reflux, 24 h, 71%; (b) TFA, DCM, 0 °C to rt, 12 h, 92%.

Scheme 29

Synthesis of 4-trifluoromethanesulfonamidyl prolinol tert-butyldiphenylsilyl ether 60. Reagents and conditions: (a) SOCl₂, MeOH, 0 °C to 40 °C, 2 h; (b) Boc₂O, Na₂CO₃, THF/H₂O (3:1), 0 °C to rt, 12 h; (c) PhCOOH, Ph₃P, DIAD, THF, 0 °C to rt, 12 h; (d) LiOH∙H₂O, THF/MeOH/H₂O (1:1:1), 0 °C to rt, 12 h; (e) Me₂SO₄, K₂CO₃, acetone, 0 °C to rt, 12 h, 81% over five steps; (f) MsCl, Et₃N, DCM, 0 °C to rt, 12 h, 97%; (g) NaBH₄, THF/MeOH, 0 °C to rt, 12 h, 99%; (h) TBDPSCl, imidazole, DCM, 0 °C to rt, 12 h, 95%; (i) NaN₃, DMF, 70 °C, 12 h, 86%; (j) (i) Ph₃P, THF, rt, 4 h; (ii) H₂O, 80 °C, 12 h, 81%; (k) Tf₂O, DIPEA, DCM, −78 °C to rt, 12 h, 70%; (l) TFA, DCM, 0 °C, 6 h, 76%.

Scheme 30

Synthesis of binaphthyl sulfonimide pyrrolidine 61. Reagents and conditions: (a) (i) NaH, DMF, 0 °C, 2 h; (ii) N,N-dimethylthiocarbamoyl chloride, 85 °C, 4 h, 69%; (b) MW (300 W), 200 °C, 20 min, 65%; (c) N-chlorosuccinimide, 2 M HCl/CH₃CN, 0 °C to 10–20 °C, 30 min; 87%; (d) DCM, Et₃N, rt, 12 h; (e) TFA, DCM, rt, 4 h, 41% over two steps.

Scheme 31

Synthesis of sugar-based pyrrolidine 62. Reagents and conditions: (a) (i) Ph₃P, I₂, imidazole, DCM, rt, 2 h; (ii) NaN₃, DMF, rt, 5 h, 67% over two steps; (c) diacetone-D-glucose, NaH, THF, rt to 70 °C, 2 h, 76%; (d) CuI (20 mol%), DIPEA, CHCl₃/EtOH/H₂O (9:1:1), rt, 16 h; (e) DMF/piperidine, rt, 30 min, 78% over two steps.

Scheme 32

Synthesis of aminophosphonic acid monoester pyrrolidine 63. Reagents and conditions: (a) LiAlH₄, THF, reflux, 2 h, >99%; (b) CbzCl, Et₃N, DCM, rt, 18 h, 63%; (c) MsCl, Et₃N, DCM, 0 °C to rt, 3 h; (d) NaI, acetone, reflux, 12 h; (e) (EtO)₂P(O)H, NaH, DMF, 55 °C, 5 days, 76% over three steps; (f) LiBr, CH₃CN, reflux, 15 h; (g) 0.6 M HCl, rt, 30 min; (h) H₂ (1 atm), Pd(OAc)₂ (20 mol%), EtOH, rt, 4 days, 88% over three steps.

Scheme 33

Synthesis of sulfone pyrrolidine 64. Reagents and conditions: (a) Et₃N, (Boc)₂O, DCM, 0 °C, 2.5 h, 94%; (b) BH₃∙THF, THF, 0 °C, 2 h, rt, 1 h, 82%; (c) TsCl, pyridine, 0 °C, 4 h, 92%; (d) (i) 2-naphthalenethiol, NaH, THF, 0 °C, 5 min; (ii) O-tosyl-pyrrolidinol, reflux, 5 h, 76%; (e) mCPBA, DCM, rt, 2.5 h, 90%; (f) TFA, DCM, rt, 5 h, 90%.

Scheme 34

Synthesis of thiourea-amine bifunctional organocatalyst 65. Reagents and conditions: (a) CS₂, DCC, Et₂O, 0 °C to rt, 3 h, rt 12 h, 76%; (b) Ph₃P, HN₃/benzene, DIAD, THF, 5 °C to rt, 3 h; (c) (i) Ph₃P, THF, 40 °C; (ii) H₂O, rt, 3 h, 61% over two steps; (d) DCM, rt, 9 h, 88%; (e) DCM, TFA, 12 h, rt, 55%.

Scheme 35

Synthesis of bifunctional 2-amino-pyridine pyrrolidine organocatalyst 66. Reagents and conditions: (a) CbzCl, NaOH, 0 °C, 4 h, 87%; (b) SOCl₂, reflux, 2 h, 99%; (c) 2-aminopyridine, Et₃N, DCM, 0 °C, 12 h, 74%; (d) H₂ (1 atm), Pd/C (10%, w/w), CH₃OH, 24 h, 92%; (e) LiAlH₄, THF, rt, 24 h, 74%.

Scheme 36

Synthesis of 1H-benzo[d]imidazole-pyrrolidine bifunctional organocatalyst 67. Reagents and conditions: (a) BnBr, Et₃N, DCM, 8 h, 99%; (b) LiAlH₄, THF, 0 °C to rt, 20 h, 97%; (c) (i) Ph₃P, phtalimide, THF, 10 min; (ii) DEAD, reflux, 8 h; (d) (i) hydrazine monohydrate, EtOH, reflux 2 h; (ii) HCl 1M, reflux 30 min, 70% over two steps; (e) HCl, urea, 130–140 °C, 6 h, 90%; (f) phosphoryl chloride, reflux, 2 h, 45%; (g) Et₃N, 190–200 °C, 16 h; (h) H₂ (1 atm), Pd/C (10 mol%), CH₃OH, rt, 48 h, 41% over two steps.

Scheme 37

(a) Synthesis of pyrrolidine (thio)ureas 68a–e. Reagents and conditions: (a) MeOH, SOCl₂, Et₃N, 0 °C to 40 °C, 2 h; (b) Boc₂O, Na₂CO₃, THF/H₂O (3:1), 0 °C to rt (c) PhCOOH, Ph₃P, DIAD, THF. 0 °C to rt; (d) LiOH, THF/MeOH/H₂O (1:1:1), 0 °C to rt; (e) Me₂SO₄, K₂CO₃, acetone, 0 °C, 81%; (f) MsCl, Et₃N, DCM, 0 °C to rt, 97% (g) NaBH₄, THF, MeOH, 0 °C to rt, 99%, (h) TBDPSCl, imidazole, DCM, 0 °C to rt, 95% (i) NaN_3, DCM, rt, 86% (j) (i) Ph₃P, THF, rt; (ii) H₂O, 80 °C, 81%; (k) RNCS, rt; (l) TFA, DCM, 0 °C to RT, 6 h. 40–45% over two steps. (b) All the catalysts synthetized with a similar procedure. (c) Proposed transition state.

Scheme 38

Synthesis of fluorous (S)-pyrrolidine–thiourea bifunctional organocatalyst 69. Reagents and conditions: (a) DIPEA, pyridine, DCM, 58%; (b) TFA, DCM, 95%.

Scheme 39

(a) Synthesis of organocatalysts 70a and 71a–d. Reagents and conditions: (a) CSCl₂, DCM, aq. NaHCO₃; (b) tert-butyl (S)-2-(aminomethyl)pyrrolidine-1-carboxylate, DCM; (c) 6 N HCl/MeOH, AcOH, 100 °C, 3 h, 70a: 88%, 71a: 76%, 71b: 72%, 71c: 80%, 71d: 85%. (b) Transition state for catalyst 70a.

Scheme 40

Synthesis of pyrrolidinyl-sulfamide organocatalysts 72a–d and 73a–d. Reagents and conditions: (a) Et₃N, DCM, 0 °C; (b) tert-butyl (S)-2-(aminomethyl)pyrrolidine-1-carboxylate, DCE, reflux; (c) TFA, DCM, 0° C to rt; (d) tert-butyl (S)-2-(aminomethyl)pyrrolidine-1-carboxylate, Et₃N, DCM, 0 °C; (e) DCE, reflux.

Figure 26

Organocatalysts composed of the polyoxometalate acid and chiral diamines 74a–e.

Scheme 41

(a) Simultaneous dual activation of aldehydes and nitroolefins obtained employing catalyst type 75. (b) Synthesis of squaramide-based aminocatalysts 75a,b. (c) Asymmetric Diels–Alder reaction of anthracenes using nitroalkenes as dienophiles.

Scheme 42

Synthesis of organocatalysts 76 and 77. Reagents and conditions: (a) Boc₂O_, 83%; (b) ClCO₂C₂H₅, Et₃N, DCM then (R)-α-methylbenzyl amine, 85%; (c) HCOOH, 80%; (d) LiAlH₄, 70%.

Scheme 43

Synthesis of organocatalysts 78a–d.

Scheme 44

Synthesis of organocatalyst 79. Reagents and conditions: (a) Me₂S BH_3, THF, 0 °C to rt, 92%; (b) TsCl, pyridine, 0 °C, 91%; (c) NaH, THF, 0 °C; PhSH, reflux, 5 h, 83%; (d) NaIO₄, MeOH/H₂O, 0 °C to rt, 92%; (e) TFA, DCM, 5 h, rt, 89%.

Scheme 45

Synthesis of organocatalyst 80a,b. Reagents and conditions: (a) THF, reflux, 23 h, 80a: 98%, 80b: 84%; (b) For 80a: tert-butyl (R)-2-(aminomethyl)pyrrolidine-1-carboxylate, THF, reflux, 20 h; for 80b: tert-butyl (R)-2-(aminomethyl)pyrrolidine-1-carboxylate, THF, reflux, 50 h, 89%; (c) For 80a: TFA, DCM, rt, 30 min, 34% over the two steps; For 80b: TFA, DCM, rt, 3 h, 75%.

Scheme 46

Synthesis of organocatalyst 81 and proposed stereochemical model for the Michael addition of ketones to nitroolefins. Reagents and conditions: (a) (i) SOCl₂, MeOH, rt to 45 °C, 6 h; (ii) Boc₂O, rt, 16 h, 95% over the two steps; (b) DAST, DCM, −78 °C, 16 h, 78%; (c) DIBAL-H, DCM, −78 °C, 6 h, 68%; (d) pyrrolidine, NaBH₃CN, 4Å MS, MeOH, 0 °C, 12 h, 54%; (e) (i) HCl/Et₂O, rt, overnight; (ii) 1M NaOH, rt, 2 h, 90% over two steps.

Scheme 47

Synthesis of organocatalysts 70b–d. Reagents and conditions: (a) (i) MsCl, Et₃N, DCM; (ii) PhCOONa, DCM, 90 °C; (iii) K₂CO₃, MeOH; (b) TBDMSCl, imidazole, DCM, rt; 82–88%; (c) DAST, DCM, −78 °C, 67–77%; (d) DIBAL-H, DCM, −78 °C, 51–61%; (e) MsCl, Et₃N, DCM; (f) NaN₃, DMF; 47–73% over two steps; (g) (i) PPh₃, THF 65 °C; (ii) H₂O, 65 °C; (h) methyl (S)-3-isothiocyanato-3-phenylpropanoate, 46–71% over two steps; (h) HCl 6 N/MeOH, AcOH; 70b: 64%, 70c: 92%, 70d: 44%, 70e: 55%.

Scheme 48

Synthesis of organocatalysts 82a,b. Reagents and conditions: (a) EDC, HOBt, DCM, rt, 8 h, I-25a: 81%, I-25b: 81%; (b) Pd/C, H₂ (1 atm), MeOH, rt, 12 h, 82a: 84%, 82b: 82%.

Scheme 49

Synthesis of organocatalysts 83a,b and transitions states for the Michael addition in water (A) and for the neat conditions in presence of p-nitrobenzoic acid (B). Reagents and conditions: (a) PPh₃, DIAD, THF, 0 °C to rt, 4–6 h, I-27a: 93%, I-27b: 90%; (b) TFA, DCM, 0 °C to rt, 3 h, 83a: 91%, 83b: 87%.

Scheme 50

Synthesis of pyrrolidine-oxytriazole catalyst 84. Reagents and conditions: (a) PPh₃, DIAD, THF, 0 °C to rt, 4–6 h, 88%; (b) TFA, DCM, 0 °C to rt, 3 h, 93%.

Scheme 51

Synthesis biaryl-based organocatalysts 85a–c.

Scheme 52

Synthesis of perhydroindolinol 89. Reagents and conditions: (a) (i) SOCl₂, MeOH, rt; (ii) LiAlH₄, THF, rt, 92% over two steps.

Scheme 53

Synthesis of pyrrolidine sulfinamide 90. Reagents and conditions: (a) (i) NaBH₄, THF, 0 °C, 1 h; (ii) BF₃∙Et₂O, 0 °C, 18 h, 93%; (b) DMSO, oxalyl chloride, Et₃N, DCM, −78 °C, 1 h, 0 °C, 30 min; (c) (S)-2-methylpropane-2-sulfinamide, CuSO₄, DCM, rt, 48 h, 89% over two steps; (d) NaBH₄, THF, 0 °C, 1 h, 86%; (e) Et₂NH, THF, rt, 2 h, 52%.

Scheme 54

Synthesis of (thio)carbamate-derived organocatalysts 91a,b. Reagents and conditions: (a) BH₃∙Me₂S, THF, 93%; (b) for 91a: isocyanatobenzene, DMAP, DCM, 91%; for 91b: isocyanatobenzene, BF₃∙Et₂O, THF, reflux, 42%; (c) HCOOC, 91a: 84%, 91b: 81%.

Scheme 55

Synthesis of organocatalyst 92a,b. Reagents and conditions: (a) for I-28a: LiAlH₄, THF, 70 °C, 3 h, 94%; for I-28b: LiBH₄, rt, 48 h, 93%; (b) Boc₂O, NaHCO₃, THF:H₂O (1:1), rt, 16 h, 58–98%; (c) TsCl, Et₃N, DMAP, DCM, rt, 16 h, 62–95%; (d) NaCN, DMSO, 80 °C, 8 h, 45–68%; (e) 50% NH₂OH (aq), EtOH, rt, 48 h; 74–83% (f) 1,1’-Carbonyldiimidazole, THF, 70 °C, 16 h; 37–63% (g) 4 M HCl in dioxane, rt, 4 h, 92a: 97%, 92b: 98%.

Scheme 56

Synthesis of thiosquaramide organocatalysts 93a–c. Reagents and conditions: (a) cyclopentanol, PhMe, reflux, 8 h, 86%; (b) Lawesson’s reagent, DCM, rt, 48 h, 62%; (c) I-30a–c, DCM, 0 °C to rt, I-30a: 80%, I-30b: not given, I-30c: 83%; (d) tert-butyl (R)-2-(aminomethyl)pyrrolidine-1-carboxylate, DCM, 0 °C to rt, 1.5 h; (e) TFA, DCM, 0 °C to rt, 1.5 h, 93a: 73%, 93b: 51%, 93c: 55% over two steps.

Scheme 57

Synthesis of N-sulfinylpyrrolidine thioureas and ureas 94a,b and 95a,b. Reagents and conditions: (a) PPh₃, DIAD, DPPA, THF, rt; (b) PPh₃, 75 °C; (c) H₂O, 56% over 3 steps; (d) CSCl₂, TEA, THF, rt, 86%; (e) bis(trichloromethyl)carbonate, DIPEA, THF, rt, 100%; (f) nBuLi, THF, 80–90% for thioureas, 24% for ureas; (g) TFA, DCM, 96–98%.

Scheme 58

Squaramide 75c and thiosquaramide 93a organocatalysts proposed by Kupai and organocatalyzed asymmetric conjugate addition.

Scheme 59

(a) Synthesis of amidomethylpyrrolidines 96. Reagents and conditions: (a) TsCl, KOH, DCM, rt, 93%; (b) NaN₃, DMF, 80 °C, 80%; (c) H₂ (1 atm), Pd/C, MeOH, rt, 94%; (d) C₆F₅SO₂Cl, Et₃N, DCM, rt, 80%; (e) 3,5-(NO₂)₂C₆H₃CH₂Br, K₂CO₃, DMF, rt, 74%; (f) TFA, DCM, rt, 90%. Yields reported for catalyst 96k. (b) Organocatalyzed cascade reaction to anti-α-carbolinol and proposed transition state. (c) Synthesized iodinated organocatalysts.

Scheme 60

Synthesis of aminal-pyrrolidine organocatalysts 98a–f. Reagents and conditions: (a) BH_3∙SMe₂, THF, 99%; (b) PCC, DCM, MS (4Å), 74%; (c) diamines, DCM, MS (4Å), K₂CO₃; (d) H₂ (1 atm), Pd/C, AcOEt, 51–82%.

Scheme 61

Synthesis of (S)-(pyrrolidin-2-yl)diphenyl methyl amine 99. Reagents and conditions: (a) SOCl₂, MeOH, 0 °C, 1 h, 100%; (b) BnBr, Et₃N, CH₂Cl₂, 25 °C, 8 h, 95%; (c) bromobenzene, Mg, THF, 25 °C, 12 h, 97%; (d) H₂SO₄/CHCl₃, NaN₃, 0 °C, 12 h, 96%; (e) LiAlH₄, THF, reflux, 8 h, 95%; (f) H₂ (60 psi), Pd/C, MeOH, 25 °C, 99%.

Scheme 62

Zhong (above) and Lee (below) one-pot synthesis of (S)-2-(azidodiphenylmethyl)pyrrolidine (100), starting from α,α-diphenyl-(S)-prolinol.

Scheme 63

Synthesis of 2-tritylpyrrolidine 101. Reagents and conditions: (a) trityllithium, −78 °C to rt, 2 h, 54%; (b) H₂ (1 atm), Pd/C, AcOH, 25 °C, 12 h, 98%; (c) (i) (S)-malic acid; H₂O/EtOH, (ii) 1N NaOH, 30%.

Scheme 64

Synthesis of silylated perhydroindolinylmethanol catalyst 102. Reagents and conditions: (a) ClCOOEt, K₂CO₃, MeOH, rt, 98%; (b) PhMgBr, Et₂O, 0 °C, 91%; (c) KOH, MeOH, 80 °C, 91%; (d) TMSCl, Et₃N, DCM, 0 °C to rt, 84%.

Scheme 65

Synthesis of di(methylimidazole)prolinol silyl ethers 103a,b. Reagents and conditions: (a) (i) 1-methyl-1H-imidazole, BuLi, THF, −78 °C to rt, 1 h; (ii) N-Boc-L-proline methyl ester, THF, −78 °C to rt, 12 h, 53%; (b) TFA, DCM, rt, 3 h, 82%; (c) TMSOTf or TESOTf, Et₃N, DCM, 0 °C to rt, 2 h, 103a: 80%, 103b: 74%.

Scheme 66

Synthesis of ionic-tagged silylated α,α-diphenyl-(S)-prolinol 104. Reagents and conditions: (a) 3-chloropropyl-dimethylchlorosilane, imidazole, DMF, 25 °C, 12 h, 81%; (b) 1-methyl-imidazole, 80 °C, 12 h, 94%; (c) LiNTf₂, H₂O/DCM, 25 °C, 2 h, 94%; (d) H₂ (1 atm), Pd/C, MeOH, 25 °C, 12 h, 90%.

Scheme 67

Synthesis of aminal-pyrrolidine organocatalysts 105a,b. Reagents and conditions: (a) SOCl₂, MeOH, 97%; (b) PPh₃, DEAD, phenol, DCM, 63%; (c) (i) DIBAL-H, toluene; (ii) diamine, DCM, MS (4 Å), K₂CO₃; (d) H₂ (1 atm), Pd/C, AcOEt, 39–42%, over two steps.

Scheme 68

Synthesis of 2-silylated pyrrolidines 106. (A) Reagents and conditions: (a) (i) sec-BuLi/(−)sparteine, Et₂O, −78 °C, 4 h; (ii) R₃SiCl, −78 °C to rt, 12 h, 66–93%; (b) HCl/Et₂O, HCl (conc.), rt, 12 h, 18–90%. (B) Reagents and conditions: (a) (i) sec-BuLi/(−)sparteine, Et₂O, −78 °C, 4 h; (ii) Ph₂Si(OMe)₂, −78 °C to rt, 12 h; (b) (i) PhLi, Et₂O, −78 °C to 0 °C, 3 h, 50% overall yield; (c) AcCl/EtOH, AcOEt, rt, 12 h, 70%.

Scheme 69

Synthesis of 2-silylated pyrrolidines 106 using fluorosilanes. Reagents and conditions: (a) (i) sec-BuLi/(−)sparteine, Et₂O, −78 °C, 5.5 h; (ii) Ph₂RSiF, −78 °C to rt, 30 min, 90–93%; (b) (i) ZnBr₂, DCM, 15 h, 85–86%; (ii) enantioenrichment (recrystallization from 99:1 DCM/MeOH or trituration with DCM/hexanes), 68–76%.

Scheme 70

Synthesis of (S)-(−)-2-(fluorodiphenylmethyl)pyrrolidine 107. Reagents and conditions: (a) SOCl₂, MeOH, reflux, 2 h; (b) BnBr, diisopropylethylamine, toluene, reflux, 24 h, 97% overall yield; (c) PhBr, Mg, THF, rt, 16 h, 93%; (d) H₂ (1 atm), HCl (aq), Pd/C, EtOH, rt, 18 h, 96%; (e) diethylaminosulfur trifluoride, DCM, rt, 6.5 h, 54%.

Scheme 71

Synthesis of fluorinated aminal-pyrrolidine organocatalysts 108a,b. Reagents and conditions: (a) SOCl₂, MeOH, 97%; (b) diethylaminosulfur trifluoride, DCM, −78 °C, 7 h, rt, 14 h, 74%; (c) (i) DIBAL-H, toluene, −78 °C, 6 h; (ii) diamine, DCM, MS (4 Å); (d) H₂ (1 atm), Pd/C, AcOEt, 57–61%, over two steps.

Scheme 72

Synthesis of densely substituted pyrrolidines 109. Reagents and conditions: (a) trans-β-nitrostyrene, sarcosine methyl ester hydrochloride, Et₃N, MgSO₄, toluene, reflux, 7 h, 56%; (b) glycine methyl ester hydrochloride, Et₃N, MgSO₄, DCM, rt, 20 h, 92%; (c) trans-β-nitrostyrene, Et₃N, LiBr, THF, rt, 3 h, 66%.

Scheme 73

Synthesis of bicyclic diarylprolinol silyl ethers 110a–d. Reagents and conditions: (a) Ph₃P, DEAD, THF, rt, 5 h; 67%. (b) ArMgBr, THF, rt, 2–8 h; 51–85%. (c) R₂SiCl₂, imidazole, DMF, rt, 18 h; 63–70%. (d) H₂ (1 atm), Pd/C, THF:MeOH (1:1), rt, 18–36 h; 55–85%.

Scheme 74

Synthesis of bifunctional pyrrolidine-thioureas 111a–d. Reagents and conditions: (a) pyridine–SO₃, DIEA, DMSO, DCM, 0 °C, 82%; (b) PhMgBr, THF, −78 °C, 58% (98:2 dr); (c) PPh₃, DEAD, DPPA, THF, rt, 80%; (d) HCl (4 M), Et₂O, rt, 85%; (e) a: EtBr, K₂CO₃, DMF, rt, 77%; b: BnBr, K₂CO₃, DMF, rt, 80%; c: HCOOH, HCHO, H₂O, 100 °C, 62%; (f) LiAlH₄, THF, rt; (g) 1-isothiocyanato-3,5-bis(trifluoromethyl)benzene, DCM, rt, 56–70%, over two steps. (h) (i) HCOOH, HCHO, H₂O, 100 °C; (ii) LiAlH₄, THF, rt; (iii) 1-isothiocyanato-3,5-bis(trifluoromethyl)benzene, DCM, rt, 45% overall yield.

Scheme 75

Synthesis of spiro-pyrrolidines 112a,b. Reagents and conditions: (a) MsCl, Et₃N, DCM, 0 °C, 5 min; (b) (R)-phenethylamine, CH₃CN, 85 °C, 8 h, 87% over two steps; (c) Au(PPh₃)Cl (0.5 mol%)/AgOTf (1 mol%), PTS, MS (4Å), DCM, reflux, 2 h, 43%; (d) H₂ (1 atm), Pd(OH)₂/C, MeOH, rt, 10 h; (e) Et₃N, Boc₂O, DCM, 0 °C to rt, 1 h; 95% over two steps; (f) NaBH₄, MeOH, 10 min; (g) TFA, DCM, rt, 3 h; (h) imidazole, TBSCl or TBDPSCl, DMF, rt, 30 min; 83% over three steps.

Scheme 76

Synthesis of fluorinated pyrrolidine 113. Reagents and conditions: (a) AcCl, MeOH, reflux, 6 h; (b) BnCl, Et₃N, DCM, reflux, 6 h, 41% over two steps; (c) trichloroisocyanuric acid, TEMPO, DCM, 0 °C, 1 h, 96%; (d) diethylaminosulfur trifluoride (DAST), DCM, 0 °C to rt, 18 h, 72%; (e) 1-bromo-3,5-bis-(trifluoromethyl)-benzene, Mg, THF, 0 °C to rt, 15 h, 96%; (f) H₂ (1 atm), Pd/C, EtOH/AcOEt (1:1), rt, 26 h, 94%; (g) (i) NaH, THF, 0 °C; (ii) chloro-(2,3-dimethylbutan-2-yl)dimethylsilane, rt, 5 h, 94%.

Scheme 77

Synthesis of diphenylprolinol methyl ether 114. Reagents and conditions: (a) DIBAL-H, DCM, −65 °C, 30 min, 96%; (b) (S)-2-methylpropane-2-sulfinamide, Ti(OiPr)₄, THF, rt, 12 h, 70%; (c) BF₃∙Et₂O (5 mol%), MeOH, reflux, 7 h, 91%; (d) (i) BuLi, TMEDA, THF, −40 °C, 30 min; (ii) sulfinimine, −78 °C, 1 h, 79%; (e) HCl/MeOH, 0 °C to rt, 4 h, 99%.

Scheme 78

Synthesis of spiro-pyrrolidine 115. Reagents and conditions: (a) NH₂OH∙HCl, NaOAc, MeOH, reflux, 4 h; (b) NiCl₂, NaBH₄, MeOH, −15 °C, 2 h, rt, 12 h; (c) Tf₂O, Et₃N, DCM, −78 °C, 30 min; (d) TFA, DCM, 0 °C, 1.5 h, 68% over four steps.