Constructing molecular complexity and diversity: total synthesis of natural products of biological and medicinal importance

Abstract

The advent of organic synthesis and the understanding of the molecule as they occurred in the nineteenth century and were refined in the twentieth century constitute two of the most profound scientific developments of all time. These discoveries set in motion a revolution that shaped the landscape of the molecular sciences and changed the world. Organic synthesis played a major role in this revolution through its ability to construct the molecules of the living world and others like them whose primary element is carbon. Although the early beginnings of organic synthesis came about serendipitously, organic chemists quickly recognized its potential and moved decisively to advance and exploit it in myriad ways for the benefit of mankind. Indeed, from the early days of the synthesis of urea and the construction of the first carbon-carbon bond, the art of organic synthesis improved to impressively high levels of sophistication. Through its practice, today chemists can synthesize organic molecules--natural and designed--of all types of structural motifs and for all intents and purposes. The endeavor of constructing natural products--the organic molecules of nature--is justly called both a creative art and an exact science. Often called simply total synthesis, the replication of nature's molecules in the laboratory reflects and symbolizes the state of the art of synthesis in general. In the last few decades a surge in total synthesis endeavors around the world led to a remarkable collection of achievements that covers a wide ranging landscape of molecular complexity and diversity. In this article, we present highlights of some of our contributions in the field of total synthesis of natural products of biological and medicinal importance. For perspective, we also provide a listing of selected examples of additional natural products synthesized in other laboratories around the world over the last few years.

Figure 1

The arrow of molecular complexity and the art and science of chemical synthesis.

Figure 2

Selected natural products synthesized in the author’s laboratories (selected references given in the text).

Figure 3

Selected natural products synthesized in the author’s laboratories (selected references given in the text).

Figure 4

Selected natural products synthesized in the author’s laboratories (selected references given in the text).

Figure 5

Highlights of the biomimetic total synthesis of endiandric acids (1982).

Figure 6

Highlights of the total synthesis of efrotomycin (1984).

Figure 7

Highlights of the total synthesis of amphotericin B (1987).

Figure 8

Highlights of the total synthesis of calicheamicin γ₁^I (1992).

Figure 9

Highlights of the total synthesis of rapamycin (1993).

Figure 10

Highlights of the total synthesis of Taxol® (1994).

Figure 11

Highlights of the total synthesis of zaragozic acid A (1994).

Figure 12

Highlights of the total synthesis of brevetoxins A and B (1983-1998).

Figure 13

Highlights of the total synthesis of epothilones (1996-2006).

Figure 14

Highlights of the total synthesis of eleutherobin and sarcodictyins A and B (1997).

Figure 15

Highlights of the total synthesis of vancomycin (1998-2002).

Figure 16

Highlights of the total synthesis of sanglifehrin A (1999).

Figure 17

Highlights of the total synthesis of bisorbicillinoids trichodimerol, bisorbibutenolide and bisorbicillinol (1999).

Figure 18

Highlights of the total synthesis of everninomicin 13,384-1 (1999).

Figure 19

Highlights of the total synthesis of CP molecules (1999).

Figure 20

Highlights of the solid phase combinatorial synthesis of benzopyran natural and designed molecules (2000).

Figure 21

Highlights of the total synthesis of colombiasin A (2001).

Figure 22

Highlights of the total synthesis of hybocarpone (2001).

Figure 23

Highlights of the total synthesis of apoptolidin (2001).

Figure 24

Highlights of the total synthesis of coleophomones B and C (2002).

Figure 25

Highlights of the total synthesis of diazonamide A (2002-2003).

Figure 26

Highlights of the total synthesis of 1-O-methyllateriflorone (2003-2004).

Figure 27

Highlights of the total synthesis of thiostrepton (2004).

Figure 28

Highlights of the total synthesis and structural revision of azaspiracid-1, -2, and -3 (2004-2006).

Figure 29

Highlights of the total synthesis of 2,2|-epi-cytoskyrin A, rugulosin and alleged structure of rugulin (2005-2007).

Figure 30

Highlights of the total synthesis of abyssomycin C and atrop-abyssomycin C (2006-2007).

Figure 31

Highlights of the total synthesis of marinomycins A, B and C (2006-2007).

Figure 32

Highlights of the total synthesis of platensimycin (2007-2010).

Figure 33

Highlights of the total synthesis of kinamycin C, F and J (2007).

Figure 34

Highlights of the total synthesis, structural elucidation, and biological evaluation of uncialamycin (2007-2010).

Figure 35

Highlights of the total synthesis and structural revision of biyouyanagins A and B (2007-2011).

Figure 36

Highlights of the total synthesis of platencin (2008-2010).

Figure 37

Highlights of the total synthesis of cortistatin A (2008-2009).

Figure 38

Highlights of the total synthesis of polyphenols hopeanol and hopeahainol A (2009).

Figure 39

Highlights of the total synthesis of bisanthraquinone antibiotic BE-43472B (2009–2010).

Figure 40

Highlights of the total synthesis of sporolide B and 9-epi-sporolide B (2009–2010).

Figure 41

Highlights of the total synthesis and structural revision of vannusals A and B (2009-2010).

Figure 42

Highlights of the total synthesis of hirsutellone B (2009).

Figure 43

Highlights of the total synthesis of haplophytine (2009).

Figure 44

Highlights of the total synthesis of dithioketopiperazines epicoccin G and 8,8|-epi-ent-rostratin (2011).

Figure 45

Advancing the art and science of total synthesis through inspirations from nature (1976–2001).

Figure 46

Selected natural products synthesized in various laboratories since 2000.

Figure 47

Selected natural products synthesized in various laboratories since 2000.

Figure 48

Selected natural products synthesized in various laboratories since 2000.

Figure 49

Selected natural products synthesized in various laboratories since 2000.

Figure 50

Selected natural products synthesized in various laboratories since 2000.