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. 2017 Nov 8;139(44):15868-15877.
doi: 10.1021/jacs.7b08749. Epub 2017 Oct 24.

Enantioselective Total Synthesis of Antibiotic CJ-16,264, Synthesis and Biological Evaluation of Designed Analogues, and Discovery of Highly Potent and Simpler Antibacterial Agents

K C Nicolaou  1 , Kiran Kumar Pulukuri  1 , Stephan Rigol  1 , Marek Buchman  1 , Akshay A Shah  1 , Nicholas Cen  1 , Megan D McCurry  1 , Kathryn Beabout  1 , Yousif Shamoo  1
Affiliations

Enantioselective Total Synthesis of Antibiotic CJ-16,264, Synthesis and Biological Evaluation of Designed Analogues, and Discovery of Highly Potent and Simpler Antibacterial Agents

K C Nicolaou et al. J Am Chem Soc. .

Abstract

An improved and enantioselective total synthesis of antibiotic CJ-16,264 through a practical kinetic resolution and an iodolactonization reaction to form the iodo pyrrolizidinone fragment of the molecule is described. A series of racemic and enantiopure analogues of CJ-16,264 was designed and synthesized through the developed synthetic technologies and tested against drug-resistant bacterial strains. These studies led to interesting structure-activity relationships and the identification of a number of simpler, and yet equipotent, or even more potent, antibacterial agents than the natural product, thereby setting the foundation for further investigations in the quest for new anti-infective drugs.

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Conflict of interest statement

Notes

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Molecular structures of antibiotic CJ-16,264 [(+)-1], its originally assigned structure [(+)-1a], and other related pyrrolizidine natural products CJ-16,367 (A), pyrrolizilactone (B), UCS-1025A (C), and UCS-1025B (D).
Figure 2
Figure 2
Synthesized analogues of antibiotic CJ-16,264 [(±)-2–(±)-6, 7, (±)-8–(±)-12, (−)-1, (−)-1b, (−)-1c, (+)-1c, (+)-1d, (−)-13–(−)-15, (+)-16, (+)-7, (+)-17, (−)-18, (+)-19, (+)-8, and (+)-20].
Figure 3
Figure 3
Previous strategy employed in the first total synthesis of CJ-16,264 [(+)-1] presented in retrosynthetic format; TBS = tert-butyldimethylsilyl.
Figure 4
Figure 4
Previous approaches to the racemic iodo pyrrolizidinone core [(±)-21, panel A], enantiopure iodo pyrrolizidinone core [(−)-21, panel B] and [(−)-21, panel C].
Figure 5
Figure 5
Proposed enantioselective synthesis of iodo pyrrolizidinone (+)-21 based on diastereofacial iodolactonisation strategy.
Scheme 1
Scheme 1. Enantioselective Iodolactonization of Amide Derivatives to Iodo Pyrrolizidinone (+)-21a
aReagents and conditions: (a) (±)-29 (1.0 equiv), 34a (1.2 equiv), PivCl (1.05 equiv), LiCl (1.7 equiv), Et3N (2.5 equiv), CH2Cl2, −20 °C, 6 h, 35a+36a (82%, 1:1 dr); (b) (±)-29 (1.0 equiv), 34b (1.2 equiv), PivCl (1.05 equiv), LiCl (1.7 equiv), Et3N (2.5 equiv), CH2Cl2, −20 °C, 6 h, 35b+36b (87%, 1:1 dr); (c) (±)-29 (1.0 equiv), EDCI (1.5 equiv), HOAt (1.0 equiv), 34c (2.0 equiv), i-Pr2NEt (3.0 equiv), CH2Cl2, 0 → 25 °C, 16 h, 35c+36c (68%, 1:1 dr); (d) (±)-29 (1.0 equiv), EDCI (1.5 equiv), HOAt (1.0 equiv), 34d (1.0 equiv), i-Pr2NEt (3.0 equiv), CH2Cl2, 0 → 25 °C, 24 h, 35d (42%); (e) I(sym-collidine)2ClO4 (5.0 equiv), CH2Cl2:MeOH:H2O 1:1:0.05 (v/v/v), 25°C, 7 d, 3%, (98:2 er) from 35b; 72 h, 28% (24:76 er) from 35c+36c; 47%, 73% brsm (>99:1 er) from 35d. PivCl = pivaloyl chloride; EDCI = 3-(ethyliminomethyleneamino)-N,N-dimethylpropan-1-amine, HOAt = 3-hydroxytriazolo[4,5-b]pyridine.
Scheme 2
Scheme 2. Enantioselective Synthesis of Iodo Pyrrolizidinone (+)-21a
aReagents and conditions: (a) (±)-29 (1.0 equiv), EDCI (1.5 equiv), HOAt (1.0 equiv), (−)-34d (0.6 equiv), i-Pr2NEt (3.0 equiv), CH2Cl2, 0°C, 48 h, 75% based on 34d, 45% based on (±)-29; (b) I(sym-collidine)2ClO4 (5.0 equiv), CH2Cl2:MeOH:H2O 1:1:0.05 (v/v/v), 25 °C, 72 h, 47% (73% brsm); (c) I2 (3.0 equiv), NaHCO3 aq:Et2O 1:1 (v/v), 25 °C, 24 h, 74%.
Scheme 3
Scheme 3. Total Synthesis of CJ-16,264 [(+)-1]a
aReagents and conditions: (a) (+)-21 (1.0 equiv), (−)-22 (2.0 equiv), BEt3 (1.1 equiv), toluene, −78 °C, 6 h, 82%; (b) TBAF (1.0 equiv), AcOH (1.05 equiv), THF, 0 °C, 30 min, 88%; (c) IBX (5.0 equiv), EtOAc, 70 °C, 9 h, 68%; (d) DMP (1.5 equiv), CH2Cl2, 0 → 25 °C, 2 h, 83%; BEt3 = triethyl borane, IBX = 2-iodoxybenzoic acid, DMP = Dess–Martin periodinane.
Scheme 4
Scheme 4. Synthesis of CJ-16,264 Analogues (±)-2–7a
aReagents and conditions: (a) TASF (1.8 equiv), THF, 0 °C, 5 min, 35%; (b) (±)-21 (1.0 equiv), 38 (5.0 equiv), BEt3 (1.0 equiv), toluene, −78 °C, 6 h, 83%; (c) TASF (1.5 equiv), THF, 0 °C, 5 min, 88%; (d) IBX (5.0 equiv), EtOAc, 70 °C, 6 h, 57%; (e) (±)-21 (1.0 equiv), 41 (3.0 equiv), BEt3 (1.1 equiv), toluene, −78 °C, 6 h, 72%; (f) TBAF (1.0 equiv), THF, 0 °C, 5 min, 90%; (g) IBX (6.0 equiv), EtOAc, 70 °C, 6 h, 54%; (h) (±)-21 (1.0 equiv), 44 (5.0 equiv), BEt3 (1.0 equiv), toluene, −78 °C, 6 h, quant; (i) TASF (1.5 equiv), THF, 0 °C, 5 min, 66%; (j) DMP (1.5 equiv), CH2Cl2, 0 °C, 1.5 h, 63%; (k) (±)-21 (1.0 equiv), 47 (3.0 equiv), BEt3 (1.1 equiv), toluene, −78 °C, 6 h, quant; (l) TASF (1.5 equiv), THF, 0 °C, 5 min, 56%; (m) DMP (1.5 equiv), CH2Cl2, 0 °C, 1.5 h, 61%; (n) (±)-21 (1.0 equiv), 50 (3.0 equiv), BEt3 (1.0 equiv), toluene, −78 °C, 6 h, 81% (1:1 dr); (o) TASF (1.5 equiv), THF, 0 °C, 5 min, 68% (1:1 dr); (p) DMP (1.5 equiv), CH2Cl2, 0 °C, 1.5 h, 63% (1:1 dr); TASF = tris(dimethylamino)sulfonium difluorotrimethylsilicate.
Scheme 5
Scheme 5. Synthesis of CJ-16,264 Analogues (±)-8 and (±)-9 (A) and Tentative Mechanism for the Formation of (±)-9 (B)a
aReagents and conditions: (a) (±)-21 (1.0 equiv), 53 (3.0 equiv), BEt3 (1.0 equiv), toluene, −78 °C, 6 h, 84%; (b) TBAF (1.0 equiv), THF, 0 °C, 5 min, 72%; (c) DMP (1.5 equiv), CH2Cl2, 0 °C, 1.5 h, (±)-8 (24%), (±)-9 (11%); (d) IBX (5.0 equiv), EtOAc, 70 °C, 5 h, 58%; compound VI is a common contaminant of Dess–Martin reagent, either arising from incomplete acetylation of IBX during its preparation or due to partial hydrolysis of DMP; TBAF = tetra-n-butylammonium fluoride.
Scheme 6
Scheme 6. Synthesis of CJ-16,264 Analogue (±)-10a
aReagents and conditions: (a) (±)-42 (1.0 equiv), 59 (6.0 equiv), Grubbs II catalyst 56 (0.10 equiv), CH2Cl2, 40 °C, 24 h, 48%, 86% brsm; (b) TBAF (1.0 equiv), THF, 0 °C, 5 min, 62%; (c) IBX (5.0 equiv), EtOAc, 70 °C, 2 h, 24%; d) 57 (1.0 equiv), (COCl)2 (2.0 equiv), CH2Cl2, 0 → 25 °C, 3h; Et3N (3.0 equiv), morpholine (2.0 equiv), CH2Cl2, 0 → 25 °C, 9 h, 75%; (e) LiAlH4 (2.0 equiv), THF, 85°C, 12 h, 80%.
Scheme 7
Scheme 7. Synthesis of CJ-16,264 Analogue (±)-11a
aReagents and conditions: (a) 62 (3.0 equiv), Grubbs II catalyst 56 (0.2 equiv), CH2Cl2, 25 °C, 24 h, 63%; (b) TBAF (1.0 equiv), AcOH (2.0 equiv), THF, 0 °C, 5 min, 82%; (c) MNBA (1.4 equiv), DMAP (3.0 equiv), CH2Cl2, 25 °C, 12 h, 84%; (d) IBX (5.0 equiv), EtOAc, 70°C, 7 h, 48%; MNBA = 2-methyl-6-nitrobenzoic anhydride, DMAP = N,N-dimethylpyridin-4-amine.
Scheme 8
Scheme 8. Synthesis of CJ-16,264 Analogue (±)-12a
aReagents and conditions: (a) 40 (1.0 equiv), 66 (1.0 equiv), 67 (1.0 equiv), Et3N (3.0 equiv), DMAP (2.0 equiv), CH2Cl2, 0 °C, 3 h, 39%; (b) IBX (5.0 equiv), EtOAc, 70 °C, 6 h, 47%.
Scheme 9
Scheme 9. Synthesis of CJ-16,264 Analogue (−)-13a
aReagents and conditions: (a) DMP (3.0 equiv), CH2Cl2, 0 → 25 °C, 45 min, 61% (ca. 1:1 dr); (b) TASF (10 equiv), THF, 0 °C, 5 min, 33%.
Scheme 10
Scheme 10. Synthesis of CJ-16,264 Analogues (−)-15, (+)-17, and (+)-7a
aReagents and conditions: (a) (+)-21 (1.0 equiv), 71 (3.0 equiv), BEt3 (1.3 equiv), toluene, −78 °C, 6 h, 66%; (b) TBAF (1.0 equiv), THF, 0°C, 5 min, 67%; (c) DMP (1.5 equiv), CH2Cl2, 0 °C, 1.5 h, 55%; (d) (+)-21 (1.0 equiv), 72 (3.0 equiv), BEt3 (1.3 equiv), toluene, −78 °C, 6 h, 81%; (e) TBAF (1.0 equiv), THF, 0 °C, 5 min, 64%; (f) DMP (1.5 equiv), CH2Cl2, 0 °C, 1.5 h, 60%; (g) (+)-21 (1.0 equiv), 73 (3.0 equiv), BEt3 (1.3 equiv), toluene, −78 °C, 6 h, 70%; (h) TBAF (1.0 equiv), THF, 0 °C, 5 min, 77%; (i) DMP (1.5 equiv), CH2Cl2, 0 °C, 1.5 h, 60%.
Scheme 11
Scheme 11. Synthesis of CJ-16,264 Analogue (+)-17a
aReagents and conditions: (a) 81 (2.1 equiv), 80 (1.0 equiv), LDA (4.0 equiv), LiCl (12.7 equiv), THF, 0 °C, 24 h, 85%; (b) LDA (3.9 equiv), H3N·BH3 (4.0 equiv), THF, 0 → 25 °C, 6 h, 72%; (c) DMP (1.5 equiv), CH2Cl2, 0 → 25 °C, 1 h, 82%; (d) (+)-21 (1.0 equiv), 84 (3.0 equiv), BEt3 (1.3 equiv), toluene, −78 °C, 6 h, 63%; (e) TBAF (1.3 equiv), THF, 0 °C, 5 min, 85%; (f) DMP (1.5 equiv), CH2Cl2, 0 °C, 2 h, 61%; LDA = lithium diisopropylazanide.
Scheme 12
Scheme 12. Synthesis of CJ-16,264 Analogue (+)-18 and (+)-19a
aReagents and conditions: (a) (+)-21 (1.0 equiv), 87 (3.0 equiv), BEt3 (1.0 equiv), toluene, −78 °C, 6 h, 83%; (b) TBAF (1.1 equiv), AcOH (1.1 equiv), THF, 0 °C, 15 min, 87%; (c) DMP (2.0 equiv), CH2Cl2, 0 → 25 °C, 3 h, (−)-18 (46%), (+)-19 (11%, one C7′ epimer); (d) IBX (5.0 equiv), EtOAc, 70 °C, 7 h, 83%; (e) DMP (6.0 equiv), CH2Cl2, 25°C, 6 h, 58%.
Scheme 13
Scheme 13. Synthesis of CJ-16,264 Analogues (+)-8 and (+)-20a
aReagents and conditions: (a) (+)-21 (1.0 equiv), 53 (2.0 equiv), BEt3 (1.3 equiv), toluene, −78 °C, 6 h, 77%; (b) TBAF (1.0 equiv), THF, 0 °C, 5 min, 66%; (c) MnO2 (40 equiv), CH2Cl2, 25 °C, 10 h, 39%, 72% brsm; (d) (+)-21 (1.0 equiv), 90 (2.0 equiv), BEt3 (1.3 equiv), toluene, −78 °C, 6 h, 69%; (e) TBAF (1.0 equiv), THF, 0 °C, 5 min, 67%; (f) MnO2 (40 equiv), CH2Cl2, 25 °C, 10 h, 44%, 66% brsm.
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