Abstract
Total syntheses of the labdane diterpene lactones marrubiin, marrulibacetal, desertine, marrulibacetal A, marrubasch F, cyllenine C, marrulanic acid, and marrulactone are described. The trans-decalin moiety of these molecules was constructed in a stereoselective manner by a Pauson-Khand reaction, and the resultant cyclopentenone was oxidatively cleaved for formation of the lactone ring. Elongation of the side chain at C9 was achieved by an epoxide-opening reaction with a variety of nucleophiles, and the functional group manipulations completed the syntheses of these natural products. Stereochemistries of desertine could be established by the transformations.
Highlights
Flowering plants of the genus Marrubium (Lamiaceae) are distributed in the Mediterranean and temperate regions of the Eurasian zone, and most of the plants are used in folk medicine [1].The therapeutic properties of these herbs, including anti-inflammatory, hypoglycemic, analgesic, antispasmodic, vasorelaxant, and anti-diabetic effects, are attributed in part to marrubiin (1), which was first isolated in 1842 from Marrubium vulgare and is a prominent member of the labdane diterpene lactones [2] (Figure 1)
C9 C9 sideside chain latelate in in thethe synthesis by by a nucleophilic ring-opening intermediate 22, which could be derived from ester 23 through a chemoselective reduction of the ester advanced epoxide intermediate which could derived from ester through a chemoselective advanced epoxide intermediate
Total syntheses of eight labdane diterpene lactones, marrubiin (1), marrulanic acid (10), cyllenine C (12), marrulibacetal (13), marrulactone (14), marrulibacetal A (17), desertine (18), and marrubasch F (19), have been accomplished
Summary
The therapeutic properties of these herbs, including anti-inflammatory, hypoglycemic, analgesic, antispasmodic, vasorelaxant, and anti-diabetic effects, are attributed in part to marrubiin (1), which was first isolated in 1842 from Marrubium vulgare and is a prominent member of the labdane diterpene lactones [2] (Figure 1) This furanoid natural product, formed from premarrubiin (2), was reported to inhibit KCl-induced contraction of the rat aorta in a concentration-dependent manner [3]. A (15) and B (16) [13], marrulibacetal A (17), desertine (18) [14], and marrubasch F (19) [15] have been reported to date [16] These natural products are biosynthesized from (E,E,E)-geranylgeranyl diphosphate (GGPP) through peregrinol diphosphate synthase (CPS1)-catalyzed bicyclization, followed by 9,13-epoxylabd-14-ene synthase (ELS)-catalyzed formation of tetrahydropyran and regiospecific oxygenations with P450s [17,18]. Despite their remarkable biological activities, only a total synthesis of marrubiin (1) in a racemic form [19] and semi-syntheses of premarrubiin (2), marrulibanoside (9), marrubasch F (19) and (13R)-9α,13α-epoxylabda-6β(19), (15)-diol dilactone from marrubiin (1) have been reported by Mangoni and co-workers [20]
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