Towards the Total Synthesis of 3-Hydroxyvibsanin E

Abstract

In 1999 Fukuyama reported the isolation of 3-hydroxyvibsanin E (1) (Figure 1) from Viburnum awabuki 1 with an additional finding in Viburnum suspensum three years later. 2 Across the entire spectrum of vibsane natural products α-hydroxylation is very rare, 3,4 occuring only at position 3 of the bridged 7-membered ring class [e.g. 3-hydroxy-15-Omethylcyclovibsanin A (2), 5 furanovibsanin A (3), 6 and 3-O-methylfuranovibsanin A (4)6] ( Figure 1). Although, the assumed later stage p450 enzymatic oxidation 7 to introduce the single hydroxyl group at position 3 is biosynthetically elegant it posses a considerable increase in the degree of synthetic challenge over the non-hydroxylated family members. Recently, we disclosed a combined effort which resulted in the total syntheses of both (−)-epi-5-vibsanin E (5) 8 and (±)-vibsanin E (6). 9 On this basis we felt that the methodology devised to prepare 5 and 6, and the experience gained from individual efforts 10,11 on other vibsane natural products, could be applied to the more challenging hydroxylated family members, specifically 3-hydroxyvibsanin E (1) (Figure 1).Key to this endeavour would be the use of Davies' tricyclic advanced intermediate 7, 10 generated by means of two cycloadditions: 1) a rhodium-catalysed [4+3] cycloaddition to give 8 from 9, and 2) a subsequent heteronuclear [4+2] cycloadditon (Scheme 1). The tricyclic intermediate 7 has been effectively used in the synthesis of both (−)-epi-5-vibsanin E (5) 8 and (±)-vibsanin E (6) 9 as summarized in scheme 1. In order to apply 7 to the synthesis of 3-hydroxyvibsanin E (1), a regioselective C-H hydroxylation of one of the intermediates in Scheme 1 would be required. 12 In this paper, we summarize the model studies to develop a selective C-H hydroxylation, followed by its application to studies toward the total synthesis of (±)-3-hydroxyvibsanin E (1).Several reasonable approaches are available for the selective C-H hydroxylation of vibsane-related intermediates. Williams reported11f that Koser's reagent 13 [PhI(OH)(OTs)] was superior to that of Davis' reagent (PhCHONSO 2 Ph) 14 in producing 16, when investigating α-hydroxylation of tricycle 15. In the case of 7, however, Davies 10b found that the Davis' reagent was superior affording 17 in 53% yield. 10b Williams 11g found that a vastly improved protocol over both of the above procedures was the Rubottom oxidation 15 of 18 giving 19 in 80% yield (Scheme 2).With this knowledge in-hand the approach shown in scheme 3 toward 3-hydroxyvibsanin E (1) was taken. The stereospecfic cuprate addition product 10 8 was doubly deprotected to unmask the ketone and primary alcohol. Treatment of 20 with t-butyldimethylsilyl * c.williams3@uq.edu.au. NIH Public AccessAuthor Manuscript Synthesis (Stuttg). Author manuscript; available in PMC 2010 September 1. Figure 2), which occurred in high yield (71% over three steps) (Scheme 3).O-Allylation of the lithium enolate derived from 24 proceeded smoothly in 81% yield. The Claisen rearrangement occurred in only moderate yield to g...

The Future of Retrosynthesis and Synthetic Planning: Algorithmic, Humanistic or the Interplay?

“…3). [120] Collective Total Synthesis The term collective total synthesis is a fairly new concept that was first put forward by MacMillan in 2011, when his group achieved the synthesis of six alkaloids from the same advanced intermediate. [121] MacMillan argued that although syntheses targeting an advanced core structure applicable to the synthesis of closely related natural products within a family had been previously reported, it was much less common to find examples where the preparation of an advanced intermediate with appropriate functionality was amenable to the construction of structurally diverse natural products in different families, the latter constituting the definition of the term collective total synthesis, which has analogies with a biosynthetic pathway providing collections of metabolites.…”