Total (bio)synthesis: strategies of nature and of chemists

Abstract

The biosynthetic pathways to a number of natural products have been reconstituted in vitro using purified enzymes. Many of these molecules have also been synthesized by organic chemists. Here we compare the strategies used by nature and by chemists to reveal the underlying logic and success of each total synthetic approach for some exemplary molecules with diverse biosynthetic origins.

Fig. 1

Molecular structures of (+)-5-epi-aristolochene (2) and (−)-premnaspirodiene (3)

Fig. 2

Biosynthetic route to terpenes. Geranyl diphosphate (5); farnesyl diphosphate (6); geranylgeranyl diphosphate (7); (−)-limonene (8); (−)-camphene (9); taxadiene (10); casbene (11); capsidiol (12). IPP = isopentenyl diphosphate, DMAPP = dimethylallyl diphosphate

Fig. 3

Proposed mechanisms for the formation of (+)-5-epi-aristolochene (2) and (−)-premnaspirodiene (3) from farnesyl-diphosphate (6) by the action of TEAS and HPS, respectively

Fig. 4

Synthesis of (+)-5-epi-aristolochene (2) from the natural product capsidiol (12)

Fig. 5

Synthetic route to (−)-premnaspirodiene (3)

Fig. 6

Four enzymes (one salicylate-AMP ligase YbtE/PchD, two NRPS and/or NRPS/PKS enzymes HMWP1/PchE and HMWP2/PchF, and one reductase YbtU/PchG) are required for the in vitro biosynthesis of (a) yersiniabactin (24) and (b) pyochelin (25). (c) The initial stages of 24 and 25 biosynthesis proceed via a similar mechanism from chorismic acid 26 to the salicylatebisthiazole intermediate 33

Fig. 7

Biosynthesis of (a) 24 and (b) 25 from intermediate 33. One molecule of 24 can bind ferric iron while two molecules of 25 are required for Fe³⁺ chelation

Fig. 8

Chemical route to aldehyde 42, an intermediate in 24, 25, and 58 synthesis

Fig. 9

The thiazoline intermediate (43) from micacocidin (41) and yersiniabactin (24) synthesis derived from l-cysteine (29) [76, 77]

Fig. 10

Synthesis of 24 via condensation of aldehyde 42 with the micacocidin (41) synthesis intermediate 43

Fig. 11

Synthesis of 25 via (a) intermediate 42, also utilized in 24 and 58 synthesis and (b) a biomimetic strategy from salicylnitrile 61 and l-cysteine 29

Fig. 12

The initial stages of 64, 65, and 66 biosynthesis proceed via the same mechanism, with the condensation of DHB (75) (from chorismic acid 26) with a PCP-tethered amino acid 80 (serine (a), lysine (b), or threonine (c), respectively)

Fig. 13

(a) Three enzymes (EntE, EntB and EntF) are required for the in vitro reconstitution of 64. (b) Biosynthesis of 64 by the stepwise condensation of three ArCP-bound DHB groups (79) and three PCP-bound l-serines (80a). Enterobactin (64) chelates ferric iron with high affinity via the six phenolate hydroxyl groups

Fig. 14

Biosynthesis of microcin E492 (71), salmochelin S4 (67), and salmochelin SX (70) from the enterobacin (64) precursor

Fig. 15

The first chemical synthesis of 64, which involves the condensation of three serine derivatives (86) with subsequent cyclization and addition of DHB groups

Fig. 16

Chemical syntheses of 64 via (a) the first and (b) the currently most efficient organotin template strategies

Fig. 17

Total synthesis of salmochelin SX (70)

Fig. 18

(a) Total in vitro biosynthesis of 65 requires three enzymes, MxcE, MxcF, and MxcG. (b) Biosynthesis of 65 and 103 from two ArCP-bound DHB units (79) and one PCP-bound lysine (80b)

Fig. 19

(a) Total in vitro biosynthesis of 66 requires three enzymes, VibE, VibF, and VibH. (b) Biosynthesis of 66 from three ArCP-bound DHB units (79), two PCP-bound threonines (80c), and one norspermidine (105)

Fig. 20

Total synthesis of 65 from t-Boc protected lysine (108)

Fig. 21

Total synthesis of 66 via the original chemical synthesis route

Fig. 22

Total synthesis of 66 via a biomimetic strategy

Fig. 23

Staurosporine (121) and related molecules

Fig. 24

Proposed biosynthetic route to 1 from l-tryptophan (123)

Fig. 25

A sample of synthetic routes (a–c) to the staurosporine aglycone (1) with biomimetic “features”

Fig. 26

A selection of synthetic routes (a–c) to the staurosporine aglycone (1) lacking biomimetic “features”

Fig. 27

Pyocyanin (160) is a phenazine (161) natural product

Fig. 28

Overall biosynthetic route to pyocyanin (160)

Fig. 29

Synthetic route to pyocyanin (160)

Fig. 30

Selection of enterocin- and wailupemycin-type natural products produced by S. maritimus

Fig. 31

Structures of mutacin (182), doxorubicin (183), and actinorhodin (184)

Fig. 32

Biosynthetic pathway leading to enterocins and wailupemycins

Fig. 33

One-pot total in vitro biosynthesis of enterocin (180) and wailupemycin F (199) and G (200)

Fig. 34

Selection of novel wailupemycin 202–204 and enterocin analogs 205–207 generated by in vitro biosynthesis using unnatural starter units 199–201

Fig. 35

Retrosynthetic analysis of wailupemycin B (181) by the Bach group

Fig. 36

Total synthesis of wailupemycin B (181)

Fig. 37

Attempted total synthesis of wailupemycin A (194) from 217, a late intermediate of the wailupemycin B (181) synthesis

Fig. 38

Examples of molecules prepared following new concepts in total synthesis: (a) intricarene (220) generated by protective group-free synthesis and (b) late-stage site-selective C–H oxidations to generate eudesmane-type terpenes like 222 or (c) to prepare the hydroxylated artemisinin derivative 223

Fig. 39

Examples for biomimetic cascade reactions in total synthesis

Fig. 40

Key steps in the chemo-enzymatic total synthesis of (+)-(R)-aureothin (233)