Syntheses and biological studies of marine terpenoids derived from inorganic cyanide

Abstract

Isocyanoterpenes (ICTs) are marine natural products biosynthesized through an unusual pathway that adorns terpene scaffolds with nitrogenous functionality derived from cyanide. The appendage of nitrogen functional groups - isonitriles in particular - onto stereochemically-rich carbocyclic ring systems provides enigmatic, bioactive molecules that have required innovative chemical syntheses. This review discusses the challenges inherent to the synthesis of this diverse family and details the development of the field. We also present recent progress in isolation and discuss key aspects of the remarkable biological activity of these compounds.

Figure 1

(A) Isonitrile-Containing Natural Products (B) General Biosynthetic Scheme (C) Representative Isonitrile Reactivity.

Figure 2

Bisabolene sesquiterpenes isolated from 2004–2014.

Figure 3

Sesquiterpenes isolated from 2004–2014.

Figure 4

Diterpene natural products isolated from 2004–2014.

Figure 5

a. Semisynthesis of monamphilectine A. b. Passerini isolation artifacts. c. Proposed biosynthesis of urea-linked sesquiterpenes. d. Copper complexation and decomplexation of isocyanoterpenes.

Figure 6

Retrosynthetic strategies to generate stereogenic sec- and tert-alkyl isonitriles.

Figure 7

Cis-/trans-isomerism of substituted decalins.

Figure 8

A hypothetical biosynthesis of 4 based on related terpene relationships.

Figure 9

Caine’s synthesis of (–)-axisonitrile-3.

Figure 10

Piers’ studies on the stereochemistry of cyclopropyl ketone reductive cleavage.

Figure 11

Hypothesized biosynthesis of 2.

Figure 12

a. Corey’s analysis of 2; b. Corey’s chemical synthesis of 2.

Figure 13

a. Yamamoto’s analysis of 2. b. Yamamoto’s chemical synthesis of 2.

Figure 14

a. Srikrishna’s analysis of 1; b. Srikrishna’s chemical synthesis of 1.

Figure 15

Ichikawa’s analysis and synthesis of 85 using a Ritter reaction.

Figure 16

Ichikawa’s polycyclization of nerolidol en route to bisabolyl amine 164.

Figure 17

Albizati’s mercury-mediated polyene cyclization and nitrile capture.

Figure 18

Shenvi's route to (−)-164 via stereoinversion of 173.

Figure 19

a. Ellman’s analysis and b. synthesis of (+)-164 using his auxiliary.

Figure 20

Amphilectenes and adocianes.

Figure 21

Corey’s retrosynthetic analysis of (+)-7,20-diisocyanoadociane (7).

Figure 22

Corey’s chemical synthesis of 7.

Figure 23

Piers’ analysis of 8 using difunctional reagent 204 as precursor to diene 201.

Figure 24

Piers’ synthesis of 8.

Figure 25

a. Miyaoka’s analysis and b. synthesis of amphilectene 183.

Figure 26

a. Shenvi’s analysis and b. synthesis of amphilectene 9 using [3]-Danishefsky dendralene 235 and a stereospecific S_N1 reaction.

Figure 27

Pitfalls of other methods for isocyanation in the synthesis of 7.

Figure 28

Retrosynthetic analysis of 11 according to Miyaoka and Yamada’s synthesis.

Figure 29

Miyaoka’s and Yamada’s synthesis of 11.

Figure 30

Wood’s analysis of 10 uses substrate control of most stereochemistry.

Figure 31

Wood’s synthesis of kalihinol C (10).

Figure 32

Miyaoka’s analysis of 12 relies on preinstalled stereocenters (e.g. 284) prior to ring building, in contrast to the hypothesized biosynthesis of 12 from 285.

Figure 33

Kalihinol F copper chelation model.

Figure 34

Small molecule/heme interactions.

Figure 35

Representative anti-malarial (Plasmodium falciparum) activity.^,,,.

Figure 36

Metal binding alone does not explain SAR.