Empirical Chiroptical Analyses of Vicinal Bromochloro Natural Products by van't Hoff's Principle of Optical Superposition: Assignment of the C-16 Configurations of Callophycols A and B.

A simple empirical method is described that allows the assignment of absolute configurations of natural products containing chiral vicinal bromochloro (VBC) units, including the bromochloro substituted isoprenyl units present in the structures of antiproliferative halomon (1a) and its halogen-swapped isomer iso-halomon (1b) from the red alga, Portieria hornemannii, and callophycols A (3) and B (4) from Callophycus serratus. The relative configurations of 3 and 4, published in 2007, were incomplete: C-16 was left unassigned. It is now shown that the additivity of molar rotations, [M](D) (herein, abbreviated [M])─a consequence of van't Hoff's principle of optical superposition─could be used to deconvolute rotatory contributions, designated as [M(X)] and [M(Y)] of the two remotely spaced chiral substructures within 3 and 4 using simple arithmetic. Input of proxy values, [M (Y(1))] and [M(Y(2))], for the two different VBC units in two equations for [M(X)] and application of a "conditional test" returns the same value for [M(X)] only when a proxy with the correct configuration is included. It is revealed that 3 and 4 have opposite configurations at the C-16 stereocenter: 16S and 16R, respectively. Two important implications lie in these findings: 3 and 4 appear to qualify as paired-regioisomers, coupled through a putative dyotropic rearrangement (DR), and the biosyntheses of other Callophycus secondary metabolites, now numbering over 50, are tightly controlled by stereoelectronic considerations including neighboring group interactions of the DR. It now appears, counter to earlier suggestions, that the chirality of Callophycus secondary metabolites, despite their high chemodiversity, are surprisingly highly conserved. Enantiofacial halogenation additions to the C═C double bonds of precursor alkenes appear to direct the formation of the remaining stereocenters at both the halogenated benzoate-decalin core and the distal VBC of 3 and 4. A consistent hypothesis is proposed to account for macrolactonizations in other Callophycus natural products including bromophycolides A and B. The conditional test of molar rotations was applied in a different context to understand the chiroptical properties and trends observed in the highly iodinated meroditerpenes, iodocallophycols A-E, also from Callophycus sp., resulting in the revision of the configuration of callophycol E from (10R,14R) to (10S,14S).