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. 2019 Apr 23;10(6):951-960.
doi: 10.1039/c9md00145j. eCollection 2019 Jun 1.

Stereoselective semi-synthesis of the neuroprotective natural product, serofendic acid

Dimitri Perusse  1 , Michael J Smanski  1
Affiliations

Stereoselective semi-synthesis of the neuroprotective natural product, serofendic acid

Dimitri Perusse et al. Medchemcomm. .

Abstract

We have recently demonstrated a synthetic biology-enabled semi-synthesis of the potent neuroprotective compound, serofendic acid. An engineered bacterium produces ent-atis-16-en-19-oic acid, which has six of eight chiral carbons configured with the appropriate stereochemistry. Setting the configuration of the C15 hydroxyl group and C16 methylene is a critical step that occurs late in each published total or formal synthesis. Here we explore the use of alternative reducing reagents, stereochemical directing agents, reaction order, and product recycling to improve the diastereoselectivity of this step. We find that installing and oxidizing the C17 methylsulfide prior to reducing the C15 ketone provides the greatest yield of the desired C15,C16 diastereomer. This represents an improved total synthesis of serofendic acid.

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Figures

Fig. 1
Fig. 1. Summary of previous approaches for setting C15/C16 configuration. (A) Chemical structure of serofendic acids 1. (B) Efficiency of reactions and key intermediates used to establish C15/C16 configuration by Terauchi et al. (left) and Toyota et al. (right).
Fig. 2
Fig. 2. Synthesis of 15-hydroxy-17-methylsulfenyl-ent-atisan-19-oic acids 9–12 from eAA 5 from Hsu, et al. Reagents and conditions: a) (PhSeO)2O, benzene, reflux, 4 h, 75%; b) NaSMe aq., THF, r.t., 1 h; c) NaBH4, EtOH, 0 °C, 30 min, 10% (from 6) 9, 30% (from 6) 10, 11% (from 6) 11, 39% (from 6) 12. Overall yield: 7.5%.
Fig. 3
Fig. 3. Cerium(iii) chloride directed reduction. (A) Proposed reaction mechanism relying on pro-trans coordination from less sterically-hindered face (epimer 7 used as an example). (B) 1H NMR of reaction mixture showing enrichment of both cis-diastereomers. Reaction mixture is a blue trace, 1H NMR shifts of isolated compounds are green (9), yellow (9 + 10), purple (11), and orange (12). (C) Possible reaction mechanism based on experimental results (epimer 7 used as an example).
Fig. 4
Fig. 4. Synthesis of 15-hydroxy-17-methylsulfinyl-ent-atisan-19-oic acids 1, 15–17 from an epimeric mixture of 7 and 8. Reagents and conditions: a) Davis oxaziridine (2-benzenesulfonyl-3-phenyloxaziridine), CHCl3, r.t., 1 h, 86%; b) DiBAl-H, ZnCl2, THF, 0 °C, 1 h, 47% 1 and 17, 53% 15 and 16 (products 1, 15–17 not isolated and conversion calculated by 1H NMR).
Fig. 5
Fig. 5. Recycling undesired diastereomers to SA 1. (A) Oxidation of methylsulfenyl group of undesired diastereomer 10 to 17-methylsulfinyl-15-oxo epimers 15A and 15B. Reagents and conditions: i) Davis oxaziridine (2-benzenesulfonyl-3-phenyloxaziridine), CHCl3, r.t., 1 h, 46% 15A, 44% 15B. (B) Oxidation of 17-methylsulfinyl-15-oxo isomer 15B to 15-keto-17-methylsulfinyl 13B. Reagents and conditions: ii) Dess Martin periodinane, H2O, CHCl3, 0 °C to r.t., 30 min, 93%. (C) Reduction of compound 13B to produce SA 1B and 15B. Reagents and conditions: iii) DiBAl-H, ZnCl2, 0 °C, 30 min, 24% 1B, 50% 15B.
Fig. 6
Fig. 6. Semi-synthesis of 1 from 5 (black arrows) including recycling of 15B into 1B (green arrows). Reagents and conditions: a) (PhSeO)2O, benzene, reflux, 4 h, 75%; b) NaSMe aq., THF, r.t., 1 h; c) Davis' oxaziridine (2-benzenesulfonyl-3-phenyloxaziridine), CHCl3, r.t., 1 h, 43% 2 steps; d) DiBAl-H, ZnCl2, THF, 0 °C, 30 min, 47% 1A + 1B, 53% 15A + 15B; e) Dess Martin periodinane, H2O, CHCl3, 0 °C to r.t., 30 min, 93%; f) DiBAl-H, ZnCl2, THF, 0 °C, 30 min, 24% 1B, 50% 15B. Overall yield of 1 from 5: 15.2% (without recycling), 17.0% (with one round of recycling).
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