Natural product anticipation through synthesis

Abstract

Natural product synthesis remains one of the most vibrant and intellectually rewarding areas of chemistry, although the justifications for pursuing it have evolved over time. In the early years, the emphasis lay on structure elucidation and confirmation through synthesis, as exemplified by celebrated studies on cocaine, morphine, strychnine and chlorophyll. This was followed by a phase where the sheer demonstration that highly complex molecules could be recreated in the laboratory in a rational manner was enough to justify the economic expense and intellectual agonies of a synthesis. Since then, syntheses of natural products have served as platforms for the demonstration of elegant strategies, for inventing new methodology 'on the fly' or to demonstrate the usefulness and scope of methods established with simpler molecules. We now add another aspect that we find fascinating, viz. 'natural product anticipation'. In this Review, we survey cases where the synthesis of a compound in the laboratory has preceded its isolation from nature. The focus of our Review lies on examples where this anticipation of a natural product has triggered a successful search or where synthesis and isolation have occurred independently. Finally, we highlight cases where a potential natural product structure has been suggested as a result of synthetic endeavours but not yet confirmed by isolation, inviting further collaborations between synthetic and natural product chemists.

Fig. 1 |. Notable examples of ‘unwitting’ natural product anticipation^–.

For these early examples, there is no evidence to suggest the synthetic chemists envisaged that these structures would be later identified as natural products. The year and corresponding author are highlighted in blue for the reported synthesis and in green for the subsequent isolation.

Fig. 2 |. Anticipation of caryophyllene-derived meroterpenoids from Psidium guajava.

a | Anticipation of psidial A (12) and psiguajadial L (13) through a multicomponent biomimetic reaction^,,,. b | Anticipation of the psiguajanones A–D (17–20) through a multicomponent biomimetic reaction, followed by reduction. c | The βα and ββ conformers of caryophyllene (7). P. guajava, Psidium guajava.

Fig. 3 |. Anticipation of incarvilleatone, mesitylene and nagelamide E.

a | Homochiral dimerization of (±)-rengyolone (22) gives the intended target, (±)-incarviditone (24), whereas heterochiral dimerization gives the anticipated natural product, (±)-incarvilleatone (25)^–. b | Photochemical retro-[2+2] cycloaddition of the SNF-4435C and SNF-4435D (33 and 34) gives mesitylene (36) and orinocin (35)^–. c | Vinylcyclobutane rearrangement of sceptrin gives the intended target ageliferin (38) and the anticipated natural product nagelamide E (39)^–. I. younghusbandii, Incarvillea younghusbandii; S. orinoci, Streptomyces orinoci.

Fig. 4 |. Anticipation of exiguamine B.

Oxidation of catechol 41 with 10 equivalents of AgO gives the intended target exiguamine A (43), whereas the use of 20 equivalents gives the anticipated natural product exiguamine B (47)^–. N. exigua, Neopetrosia exigua.

Fig. 5 |. Anticipation of ‘missing’ dimeric natural products.

a | Known dimeric xanthanolides natural products (49–51) and their biosynthetic monomer 8-epi-xanthatin (48)^–. b | Dimerization of xanthatin (52) leads to the anticipated natural products mogolides A and B (53 and 55). c | Known bisanthraquinone natural products (56–58)^–. d | Oxidative dimerization of monomer 59 leads to the anticipated natural product 2,2′-epi-cytoskyrin A (62)^–. e | Monomer 63, used by Nicolaou et al. to access rugulosin (56)^,. X. mogolium, Xanthium mogolium.

Fig. 6 |. Anticipation of 14-methylelysiapyrone A and psychotriadine.

a | Biomimetic total synthesis of the anticipated natural product, 14-methylelysiapyrone A (70)^,. b | Known bis(cyclotryptamine) alkaloids with different isomeric scaffolds^–. c | Total synthesis of a newly anticipated piperidinoindoline-type bis(cyclotryptamine) alkaloid, psychotriadine (80). P. colorata, Psychotria colorata; P. ocellatus, Placobranchus ocellatus.

Fig. 7 |. Anticipation of phototridachiahydropyrone and atrop-abyssomicin C.

a | Biomimetic total synthesis of the anticipated natural product phototridachiahydropyrone (84) via photochemical [1,3]-sigmatropic rearrangement of tridachiahydropyrone (83)^,. b | Total synthesis of the anticipated natural product, atrop-abyssomicin C (86) and its isomerization into the target natural product, abyssomicin C (89). It was also found that reduction of atrop-abyssomicin C (86) gives abyssomicin D (88), whereas reduction of abyssomicin C (89) gives iso-abyssomicin D (91), which is not a known natural product^–. E. crispata, Elysia crispata; PIFA, phenyliodine(III) bis(trifluoroacetate).

Fig. 8 |. Additional examples for anticipated natural products and suspected natural products awaiting confirmation.

a | iso-Epicolactone (92)^,, (+)-brevianamide Y (93)^–, (±)-deoxyisobruceol (94)^– and (−)-prehalenaquinone (95) are additional examples for molecules that were synthesized in the laboratory prior to their isolation. b | Cases of anticipated natural products that await isolation from natural sources: 8-epi-isoaplydactone (96), dia-angiopterlactone B (97), biyouyanagin C (98), epi-pycnanthuquinone C (99), 8-epi-homodimericin A (100), intricarene side product (101), protected dia-millingtonine (102), dia-incargranine B aglycone (103), diastereomer towards neonectrolides (104), preuisolactone precursor (105), nuphar alkaloid isomer (106), side product towards (+)-norcembrene 5 (107), monolomaiviticin A (108), 2-epi-lankacyclinol (109), 3,7-epi-massadine (110), santarubin S (111), epi-guajadial B (112), Δ^23,24-perovskone (113), epi-pungiolide A (114) and iso-aspergilasine A (115).