Recent synthetic studies on the zaragozic acids (squalestatins)

Armstrong, Alan; Blench, Toby J.

doi:10.1016/s0040-4020(02)00993-6

Cited by 60 publications

(11 citation statements)

References 67 publications

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“…Other alkyl citrate natural products have C2 side chains of increasing complexity such as CJ-13,981 (4), L-731,120 (5), 9 the viridiofungins, 10 trachyspic acid (6), 11 cinatrins, 12 citrafungins, 13 and zaragozic acid A (7). 2 Since two comprehensive reviews 14,15 have already published on the zaragozic acids, they will not be discussed here and the focus will be on all the other known members of this class.…”

Section: Introductionmentioning

confidence: 99%

Total synthesis of alkyl citrate natural products

Rizzacasa

Sturgess²

2014

Org. Biomol. Chem.

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Section: Introductionmentioning

confidence: 99%

Total synthesis of alkyl citrate natural products

Rizzacasa

Sturgess²

2014

Org. Biomol. Chem.

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“…Over 30 groups have made impressive contributions to the literature on the synthesis of these molecules. [20][21][22][23] Of a variety of approaches to the densely oxygenated 2,8-dioxabicyclo-[3.2.1]octane ring system by devising innovative strategies and tactics, the two research groups of Carreira 24,25) and Nicolaou [26][27][28][29] accomplished the first total syntheses of zaragozic acid C and zaragozic acid A, respectively, in 1994.…”

Section: Zaragozic Acidsmentioning

confidence: 99%

Total Synthesis of the Squalene Synthase Inhibitor Zaragozic Acid C

Nakamura

2005

CHEMICAL & PHARMACEUTICAL BULLETIN

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Zaragozic acids and squalestatins were documented by Merck, Glaxo, and Tokyo Noko University/Mitsubishi Kasei Corporation as part of a program aimed at identifying novel inhibitors of squalene synthase, as well as farnesyl transferase. These natural products have attracted considerable attention from numerous synthetic chemists because of their therapeutic potential and novel architecture. This review highlights our total syntheses of zaragozic acid C by two convergent strategies. The key steps in our first-generation synthesis involve 1) simultaneous creation of the C4 and C5 quaternary stereocenters through the Sn(OTf) 2 -promoted aldol coupling reaction between the a a-keto ester and silyl ketene thioacetal derived from L-and D-tartaric acids, respectively; and 2) construction of the bicyclic core structure via acid-catalyzed internal ketalization under kinetically controlled conditions. The second-generation strategy relies on a tandem carbonyl ylide formation/1,3-dipolar cycloaddition approach and features elongation of the C1 alkyl side chain through an olefin cross-metathesis as well as high convergency and flexibility.

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“…Since their isolation was reported in the early 1990s [1–2], the squalestatins/zaragozic acids (e.g., squalestatin S1/zaragozic acid A ( 1 ), Fig. 1) have been of enduring interest to synthetic chemists, due to a combination of a synthetically challenging densely functionalised 2,8-dioxabicyclo[3.2.1]octane core [3–6], combined with an increasing range of intriguing biological activities [7–11]. Here, we report in detail the evolution of chemistry that provides an asymmetric entry to the tricarboxylate core of these natural products, with particular focus on tartrate alkylation methodology to establish the fully-substituted C-5 stereocentre (squalestatin numbering).…”

Section: Introductionmentioning

confidence: 99%

Alkylation of lithiated dimethyl tartrate acetonide with unactivated alkyl halides and application to an asymmetric synthesis of the 2,8-dioxabicyclo[3.2.1]octane core of squalestatins/zaragozic acids

Sintim

Mamari

Almohseni

et al. 2019

Beilstein J. Org. Chem.

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(R,R)-Dimethyl tartrate acetonide 7 in THF/HMPA undergoes deprotonation with LDA and reaction at −78 °C during 12–72 h with a range of alkyl halides, including non-activated substrates, to give single diastereomers (at the acetonide) of monoalkylated tartrates 17, 24, 33a–f, 38a,b, 41 of R,R-configuration, i.e., a stereoretentive process (13–78% yields). Separable trans-dialkylated tartrates 34a–f can be co-produced in small amounts (9–14%) under these conditions, and likely arise from the achiral dienolate 36 of tartrate 7. Enolate oxidation and acetonide removal from γ-silyloxyalkyl iodide-derived alkylated tartrates 17 and 24 give ketones 21 and 26 and then Bamford–Stevens-derived diazoesters 23 and 27, respectively. Only triethylsilyl-protected diazoester 27 proved viable to deliver a diazoketone 28. The latter underwent stereoselective carbonyl ylide formation–cycloaddition with methyl glyoxylate and acid-catalysed rearrangement of the resulting cycloadduct 29, to give the 3,4,5-tricarboxylate-2,8-dioxabicyclo[3.2.1]octane core 31 of squalestatins/zaragozic acids. Furthermore, monoalkylated tartrates 33a,d,f, and 38a on reaction with NaOMe in MeOH at reflux favour (≈75:25) the cis-diester epimers epi- 33a,d,f and epi- 38a (54–67% isolated yields), possessing the R,S-configuration found in several monoalkylated tartaric acid motif-containing natural products.

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Recent synthetic studies on the zaragozic acids (squalestatins)

Cited by 60 publications

References 67 publications

Total synthesis of alkyl citrate natural products

Total synthesis of alkyl citrate natural products

Total Synthesis of the Squalene Synthase Inhibitor Zaragozic Acid C

Alkylation of lithiated dimethyl tartrate acetonide with unactivated alkyl halides and application to an asymmetric synthesis of the 2,8-dioxabicyclo[3.2.1]octane core of squalestatins/zaragozic acids

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