An Update on the Synthesis of Pyrrolo[1,4]benzodiazepines

Abstract

Pyrrolo[1,4]benzodiazepines are tricyclic compounds that are considered "privileged structures" since they possess a wide range of biological activities. The first encounter with these molecules was the isolation of anthramycin from cultures of Streptomyces, followed by determination of the X-ray crystal structure of the molecule and a study of its interaction with DNA. This opened up an intensive synthetic and biological study of the pyrrolo[2,1-c][1,4]benzodiazepines that has culminated in the development of the dimer SJG-136, at present in Phase II clinical trials. The synthetic efforts have brought to light some new synthetic methodology, while the contemporary work is focused on building trimeric pyrrolo[2,1-c][1,4]benzodiazepines linked together by various heterocyclic and aliphatic chains. It is the broad spectrum of biological activities of pyrrolo[1,2-a][1,4]benzodiazepines that has maintained the interest of researchers to date whereas several derivatives of the even less studied pyrrolo[1,2-d][1,4]benzodiazepines were found to be potent non-nucleoside HIV-1 reverse transcriptase inhibitors. The present review is an update on the synthesis of pyrrolo[2,1-c][1,4]benzodiazepines since the last major review of 2011, while the overview of the synthesis of the other two tricyclic isomers is comprehensive.

Keywords: DNA-interactive agents; anti-HIV activity; anticancer activity; heterocycles; pyrrolobenzodiazepines; small molecules.

Figure 1

Structure of the three pyrrolo[1,4]benzodiazepine isomers 1–3 and the first derivatives 4–7.

Figure 2

DC-81, Limazepine E and Fuligocandin B are natural products, SG2042 and SG2738 are PBD monomers, IN6CPBD is a PBD conjugate and SJG-136 is a PBD dimer.

Figure 3

A biologically active pyrrolo[1,2-d][1,4]benzodiazepine.

Scheme 1

Synthesis of estradiol derivatives.

Scheme 2

Synthesis of C8-O-substituted PBD conjugates 19a–f.

Scheme 3

Synthesis of C8-O-substituted PBD conjugates 22a–f.

Scheme 4

Synthesis of 2-methoxy-5-(piperazin-1-ylcarbonyl)phenol 29 and acid chlorides 32a–h.

Scheme 5

Synthesis of bromoalkyl derivatives 34a–h.

Scheme 6

Synthesis of C8-O-substituted PBD conjugates 38a–h.

Scheme 7

Synthesis of C8-O-substituted PBD conjugates 44a–i.

Scheme 8

Synthesis of C2-substituted PBD conjugates 49a–b.

Scheme 9

Synthesis of C8-O-substituted PBD conjugates 54a–g.

Figure 4

C8-O-substituted PBD conjugates 55a–f.

Scheme 10

Synthesis of C8-O-substituted PBD conjugates 62a–l.

Scheme 11

Synthesis of C8-O-substituted PBD conjugates 67a–f.

Scheme 12

Synthesis of imidazo[1,5-a]pyridine precursors 76a–c.

Scheme 13

Synthesis of C8-O-substituted PBD conjugates 78a–l.

Scheme 14

Synthesis of carbodithioate derivative 82.

Scheme 15

Synthesis of C8-O-substituted PBD conjugates 84a–c and 86a,b.

Scheme 16

Synthesis of C8-substituted PBD conjugates 96a–c.

Scheme 17

Synthesis of C8-O-substituted PBD conjugates 102a–f.

Scheme 18

Synthesis of aminoester precursors 107 and 109.

Scheme 19

Synthesis of C8-O-substituted PBD conjugates 111–114.

Scheme 20

Synthesis of C8-O-substituted PBD conjugates 115–118.

Scheme 21

Synthesis of C8-O-substituted PBD conjugates 124a–n.

Scheme 22

Synthesis of C8-O-protected PBD precursor 132.

Scheme 23

Synthesis of C8-OH N10-Troc C11-OAc PBD precursor 136.

Scheme 24

Synthesis of C8,C8′-linked PBD symmetric dimers 138 and 140.

Scheme 25

Synthesis of C8,C8′-linked PBD non-symmetric dimer 146.

Scheme 26

Synthesis of C8-O-substituted PBD conjugates 156a–g.

Scheme 27

Synthesis of PBD 162.

Scheme 28

Synthesis of PBD 171.

Scheme 29

Synthesis of C8-O-substituted PBD conjugates 172a–p.

Scheme 30

Synthesis of spiro PBD derivatives 176a–d, 177a,b, 178a–d and 179a,b.

Scheme 31

Synthesis of PBD derivatives 185a–d.

Scheme 32

Synthesis of PBD derivatives 191a–f.

Scheme 33

Synthesis of PBD derivatives 193 and 195.

Scheme 34

Synthesis of PBD derivatives 201, 203 and 204.

Scheme 35

Synthesis of PBD derivative 211a.

Scheme 36

Synthesis of PBD derivatives 211a–c.

Scheme 37

Synthesis of PBD derivatives 220a–o.

Scheme 38

Synthesis of PBD derivatives 223a–w.

Scheme 39

Synthesis of PBD derivatives 223–229.

Scheme 40

Synthesis of PBD derivatives 231 and 233.

Scheme 41

Synthesis of PBD derivatives 6a–g.

Scheme 42

Synthesis of PBD derivatives 237 and 238.

Scheme 43

Synthesis of PBD derivatives 6a,h.

Scheme 44

Synthesis of PBD derivatives 241–243.

Scheme 45

Synthesis of PBD derivatives 248 and 249a–o.

Scheme 46

Synthesis of PBD derivatives 255 and 256.

Scheme 47

Synthesis of PBD derivatives 261a–g.

Scheme 48

Synthesis of PBD 267.

Scheme 49

Synthesis of PBD derivatives 273a–e.

Scheme 50

Synthesis of PBD 276.

Scheme 51

Synthesis of PBD derivatives 249a–g.

Scheme 52

Synthesis of PBD 285.

Scheme 53

Synthesis of PBD derivatives 7a,b.

Scheme 54

Synthesis of PBD derivatives 290a–c.

Scheme 55

Synthesis of PBD derivatives 295c–e.

Scheme 56

Synthesis of PBD derivatives 248 and 249a–o.

Scheme 57

Synthesis of PBD derivatives 306a–f.

Scheme 58

Synthesis of PBD derivatives 312a–g and 314a–g.