Synthesis of anti and syn hydroxy-iso-evoninic acids

Abstract

The first synthesis of hydroxy-iso-evoninic acid (2), a pyridyl diacid found as a macrodilactone bridging ligand in bioactive Celastraceae sesquiterpenoid-based natural products, has been achieved in 9 steps and an overall yield of 26%. The synthesis utilizes a benzilic ester rearrangement (BER) and a late stage benzylic oxidation to give access to all four stereoisomers whose absolute stereochemistry was assigned following chromatographic separation and anomalous dispersion X-ray crystallography.

Transformation of a Chiral Glycolic Acid to an Isoaurone: Stereochemical Assignment of a Benzilic Acid Rearrangment Product

“…We then assumed that the nucleophile will attack carbonyl‐2 according to Cram's rule (or the Felkin‐Ahn model), (this was also invoked by Brady et al [6] . in their mechanistic model).…”

“…ν max (KBr)/cm −1 3436, 3369, 1762, 1613. 1 H NMR (270 MHz, DMSO‐d [6] /CDCl 3 ), 3.13 (s, 3‐OMe, 3H), 3.71 (s, 4’‐OMe, 3H), 3.94 (s, 2‐OH, 1H), 5.06 (s, 3‐H, 1H), 6.29 (d, J=2.9 Hz, 3'‐H, 1H), 6.38 (dd, J=9, 2.9 Hz, 5’‐H, 1H), 7.33 (M, 4’‐H, 3‐Ph, 6H). 13 C NMR (67.80 MHz, DMSO‐d [6] /CDCl 3 ), 54.81, 56.38, 81.05, 84.44, 101.79, 104.44, 117.38, 127.27, 128.21, 129.14, 131.08, 136.52, 157.36, 159.60, 172.90. m/z 318 (M+, 0.5), 300 (1), 268 (7), 252 (18), 196 (1), 179 (3), 151 (100), 121 (90%).…”

“…ν max (KBr)/cm À 1 3436, 3369, 1762, 1613. 1 H NMR (270 MHz, DMSO-d [6] /CDCl 3 ), 3.13 (s, 3-OMe, 3H), 3.71 (s, 4'-OMe, 3H), 3.94 (s, 2-OH, 1H), 5.06 (s, 3-H, 1H), 6.29 (d, J = 2.9 Hz, 3'-H, 1H), 6.38 (dd, J = 9, 2.9 Hz, 5'-H, 1H), 7.33 (M, 4'-H, 3-Ph, 6H). 13 C NMR (67.80 MHz, DMSO-d [6]…”

“…Of outstanding significance was the recent demonstration by Zhu and co‐workers of a catalytic asymmetric version with an acyclic system which used a well‐known chiral Cu catalyst to control the enantiofacial selectivity [4] . However, this result does not mitigate the difficulty in obtaining high diastereoselectivities in these systems that has been both demonstrated by us [5] and by other workers [6] …”

“…[4] However, this result does not mitigate the difficulty in obtaining high diastereoselectivities in these systems that has been both demonstrated by us [5] and by other workers. [6] In 1989, Brady et al [7] reported a highly stereoselective benzilic acid rearrangement on the α-diketone 5 [4,5,8] (an intermediate involved in a ring-chain tautomerism event that allows the equilibration of the two diastereomeric benzofurano-3-ones 4 a and 4 b) to give a single isomer of the αhydroxypropanoic acid product 6 which was originally assigned the (2R,3S)-configuration (Scheme 2). The authors proposed that the hydroxide attacks the α-diketone 5 at carbonyl carbon-2 in accordance with Cram's rule to form preferentially the diastereomer adduct A (Scheme 2(a)) which was hypothesised to be stabilized by intramolecular hydrogen bonding (Scheme 2 (b)) forcing it into a conformation that would afford the product (2R,3S)-6 after the 1,2-rearrangment had occurred (the authors also proposed that the carbonyl unit would be coordinated with a sodium ion, obviously to enhance the reactivity).…”