The First Total Synthesis of (±)-Saudin

Abstract

Saudin 1which was isolated from the leaves of the toxic plant Cluytia richardiana in Saudi Arabia, 1 is notable both for its unique rearranged labdane carbon skeleton as well as for its potent hypoglycemic activity. 2 The structural complexity of saudin, which contains seven stereogenic centers and six oxygenated carbons in its 13-carbon core, has stimulated interest in its total synthesis. 3 Its potential as a lead for therapeutic development makes the availability of analogues for structure-activity relationship studies an important goal.We identified the establishment of the two quaternary carbons (C-13 and C-16) in the sterically congested hexacyclic ring system of saudin 1 as the central stereochemical challenge for total synthesis. Preliminary results from our laboratory have demonstrated that the intramolecular dioxenone photocycloaddition reaction 4 leads to the establishment of that relative stereochemical relationship in a model system lacking the C-9 oxygen functionality. 5 We report herein the extension of those findings to the synthesis of a more highly functionalized photosubstrate 4 that leads to the first total synthesis of saudin in 15 steps from readily available precursors.Our retrosynthetic analysis is outlined in Scheme 1. Disconnection of the C-1 ketal of 1 leads to the hemiketal keto-acid 2. In the synthetic sense, it is important to note that the more stable equatorial orientation of the epimerizable C-4 methyl group in 1 would be established in the conversion of 2 to 1making the C-4 stereochemistry of 2 of little consequence. The furyl hemiketal 2 could in turn be derived from the addition of a furyl anion or its equivalent to lactone 3which would result from the intramolecular photocycloaddition of dioxenone 4. The δ-lactone ring in 4 serves to constrain the trisubstituted alkene, thereby ensuring the establishment of the desired C-5, C-16 relative stereochemistry as shown in photoadduct 3.

Illicium Sesquiterpenes: Divergent Synthetic Strategy and Neurotrophic Activity Studies

“…Gratifyingly, a Pd(0)-catalyzed cross coupling reaction [37] provided a solution to this challenge. Thus, chemo-selective triflation of the C-1 ketone of 30 using Comins reagent ( N -(5-chloro-2-pyridyl)triflimide) [38] followed by treatment with trimethylaluminum/Pd(PPh3) 4 [39] cleanly yielded compound 31 (57% over two steps). In turn, the C-1–C-2 double bond of 31 was selectively hydrogenated from the 〈-face (PtO 2 , H 2 , 90 bar, 24 h) to produce the desired C-1 methylated compound 32 .…”

Synthesis of the Tetracyclic Bis(acetal) Lactone Portion of Saudin

“…This natural product, exhibiting important hypoglycemic activity, was isolated from the leaves of the toxic plant Cluytia richardiana in 1985. [4,5] In recent years, related synthetic studies have been published, [6Ϫ10] including a racemic total synthesis, [11] and more recently, Boeckman's research group has achieved the first enantioselective Scheme total synthesis of (ϩ)-and (Ϫ)-Saudin, establishing its absolute configuration. [12] In our previous work, [9] we have reported the synthesis of compound 2b starting from α-tetralone (Scheme 1), which structurally resembles the caged acetalic backbone of the natural product.…”

Studies culminating in the total synthesis and determination of the absolute configuration of (−)-saudin

“…Initial model studies followed by a concise total synthesis of the racemate were reported by Winkler in 1998-1999. 3,4 In 2002, we reported the first enantioselective total synthesis of both antipodes, firmly establishing the absolute stereochemistry of natural (-)-saudin, as the the structure depicted in Figure 1. 5 Subsequent to that publication, several additional synthetic approaches have appeared including the studies of Labadie 6-8 and Stoltz.…”