Syntheses of Bile Pigments. Part 17. Synthesis of a non‐racemizable urobilin derivative

Abstract

The optically active urobilin model compound 7 was synthesized, in which Me groups instead of H-atoms are bound to the asymmetric centers, thus preventing loss of chirality by tautomerization. The key intermediate of the eleven-step synthesis of 7 is the 1,4,5,2 0-tetrahydro-lO-hydroxy-l-oxo-l1H-dipyrrin-9-carboxylate ruc-2, which could be resolved into enantiomers by fractional crystallization of the corresponding methyl N-[1 -(naphth-1-yl)ethyl]carbamates 3 and 4. The absolute configuration of enantiomerically pure (-)-2 was determined by X-ray diffraction analysis of its camphor-10-sulfonate 5. As the CD spectrum of the urobilin analogue 7 obtained from (-)-(R)-2 displays a positive Cotton effect, the present results prove, in connection with previous work, that substitution of Me groups for the H-atoms bound to the asymmetric centers of a chiral urobilin chromophore do not influence the relationship between absolute configuration of the latter and its helicity.Urobilinoids (urobilins and stercobilins) are the final products of heme catabolism in humans and mammalians [2]. This class of bile pigments deserve particular interest, however, since the existence of the urobilin chromophore was demonstrated in both algal [3] [4] and bacterial [S] accessory pigments of the phycoerythrin type, which are involved in the process of oxygenic photosynthesis in these organisms.Both urobilins and stercobilins are characterized by the presence of two asymmetric C-atoms (C(4) and C( 16) in the partially hydrogenated 22H-bilin-l,19(21H,24H)-dione chromophore). Thus, symmetrically substituted urobilins (4,5,15,16-tetrahydro-22H-bilin-I, 19(21H,24H)-diones) may be either chiral or sigmasymmetric depending on whether the relative configurations at both asymmetric C-atoms are the same or opposite, respectively (cf. 7). Chiral urobilins are characterized by the extremely high specific rotation of their hydrochlorides (e.g.[a]? = +5000 for natural d-wobilin IXa [6]), which was attributed to the presence of an inherently dissymmetric coiled dipyrrin chrornophore whose chirality is preserved by intramolecular H-bonding [7]. In this model, the helicity of the dipyrrin chromophore is determined by the absolute configurations of the asymmetric atoms C(4) and C(16). Recently, it could be proved that a (S,S)-configurated urobilin molecule displays a negative Cotton effect in the absorption range of the dipyrrin chromophore [8]. Until now, however, the precise structure of the optically active i, Part 16: 111.

Synthesis and Conformational Studies of Urobilin Difluoroboron Complexes. Unprecedented Solvent-Dependent Chiroptical Properties of the BF2 Chelate of an Urobilinoid Analogue1

“…In the present case, the circular dichroism (Δε 538 = +67) measured for the difluoroboron complex 7 , in CH 2 Cl 2 as solvent, equals that of the protonated ligand (Δε 496 = +69), its D-line specific rotation is even higher ([α] 20 D = +9700° vs +4900°) ( cf. ref ). When measured in DMF, both the circular dichroism (Δε 535 = −29) and the specific rotation ([α] 20 D = _ 3900°) of 6 are significantly lower than those of 7 , probably because of the more rigid structure of the latter, which is stabilized by intramolecular NH···F bonding, as discussed above.…”

“…Within the scope of our work on the molecular origin of the unusual chiroptical properties of urobilinoids, we have reported recently the synthesis of an optically active urobilin analogue ( 4 ) in which methyl groups instead of H atoms are bound to the stereogenic centers of the bile pigment chromophore. Although the absolute configurations at the asymmetric C atoms of both this urobilin analogue and a conventional urobilin derivative ( 3 ) 6 have been established experimentally by X-ray diffraction analysis of derivatives of the corresponding 1,4,5, 10-tetrahydro-11 H -dipyrrinones ( 2 and 1b , respectively), used as their synthetic precursors, the preferred (most likely helical) conformation of the optically active chromophores, in solution, cannot be inferred from these results.…”

Biosynthesis of porphyrins and related macrocycles. Part 45. Determination by a novel X-ray method of the absolute configuration of the spiro lactam which inhibits uroporphyrinogen III synthase (cosynthetase)

“…Since it was the illustrated Renantiomer of 10 which showed the negative C D peak, it 11 A simpler example of a monopyrrolic lactam similar to 10 which also shows a negative Cotton effect has recently been assigned the Rconfiguration by X-ray analysis (ref. 12). tt Starting with opposite enantiomer 5y as the dipyrrolic lactam, the enantiomers 49y and 51y of the above products were prepared by the same steps.…”