The Enigma of Sponge-Derived Terpenoid Isothiocyanate-Thiocyanate Pairs: A Biosynthetic Proposal

Abstract

The co-occurrence of rare terpenoid thiocyanates (R-SCN), structurally similar to their more common isothiocyanate isomers (R-NCS), poses an enigma: how does the accepted path, terpenyl cation R⁺ → R-NC → R-NCS, accommodate R-SCN? The mystery can now be rationalized by the consideration of three biosynthetic motifs: terpenoid carbocation (R⁺) capture by cyanoformate, NC-COOH (itself in equilibrium with NC^- and CO₂); co-localized rhodanese (a dual-function enzyme) that can both convert fugitive inorganic NC^- to thiocyanate ion, NCS^-, and alkyl isonitriles to alkyl isothiocyanate (R-NC → R-NCS) and adventitious capture of the NCS^- by R⁺. The former two scenarios explain the preponderance of isothiocyanates, R-NCS, as products of a linear reaction path-the α-addition of S⁰ to R-NC-and the third scenario explains minor, less stable thiocyanates, R-SCN, as products of the adventitious capture of liberated NCS^- by the penultimate R⁺ precursor. DFT calculations support this proposal and eliminate other possibilities, e.g., the isomerization of R-NCS to R-SCN.

Keywords: Porifera; alkyl isothiocyanate; alkyl thiocyanate; farnesyl pyrophosphate; geranylgeranyl pyrophosphate; isonitrile; malaria; marine natural product; nudibranch; rhodanese; thiocyanate.

Figure 1

Lewis structures (closed-shell) of terpene isonitriles (TIs), ‘isonitriloids’–isothiocyanates (ITCs), thiocyanates (TCs), carbonimidic dichlorides (CIDs), and products of reaction with H₂O formamides (FAs) and amines (As).

Figure 2

Terpenoid isonitriles (TI); kalihinols A (1a), B (1b), M (1d), and synthetic MED6-189 (1c); 7,20-diisocyanoadociane (3); and related isothiocyanates (ITCs, e.g., 1d, 2i–j, 8b and thiocyanates (TCs), 2a–d, g–k, m. bis-Isothiocyanate 12 is a non-terpenoid.

Figure 3

DFT-optimized molecular structures (ωB97X-D 6-31G*), dipole moments, key bond angles, and distances, d, of isomeric TC and ITC. (a) t-butylthiocyanate (4): µ = 4.48 D θ_thio(C-S-C) = 100.0°, d_thio(C–S) = 1.88 Å; and (b) t-butylisothiocyanate (5): µ = 6.56 D, θ_tiso(C–N_α–C) = 176.8°, d_iso(C-N_α) = 1.44 Å. The major resonance form (closed-shell Lewis structure) is depicted for each.

Figure 4

Isomerization of allylic isonitriloids, C₃H₅-NCS and C₃H₅-N₃. (a) Sigmatropic [3] rearrangements: (a) allyl thiocyanate (6a) to allyl isothiocyanate (6b). (b) Degenerate rearrangement of allyl azide (7).

Scheme 1

Proposal for the biosynthesis of sponge terpenyl isonitrile (TI), isothiocyanate (RNCS, ITC), and thiocyanate (RSCN, TC) natural products along two axes: major i and minor ii. p is the partition ratio of ITC:TC along ii.

Scheme 2

A unifying proposal for the biosynthesis of 2c, d, k with the intermediate non-classical cation i.