First Total Synthesis of (-)-Pericosine A from (-)-Shikimic Acid: Structure Revision and Determination of the Absolute Configuration of Antitumor Natural Product Pericosine A

Abstract

The first total synthesis of (-)-pericosine A, methyl (3R,4R,5R,6R)-6-chloro-3,4,5-trihydroxy-1-cyclohex-1-enecarboxylate, from (-)-shikimic acid was accomplished, which led to the revision of the relative configuration and the determination of the absolute configuration of the natural product as 3S,4S,5S,6S.

Key words

total synthesis - antitumor - natural product - pericosine A - revised structure - absolute configuration

References and Notes

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10

The stereochemistry of the new stereogenic center at C-3 in 12 was determined by the following experiments. Treatment of 12 with TFA in MeOH at r.t. gave triol 16, which was the same as the compound we synthesized as racemate.⁴ Similarly to our previous report, 12 was treated with dimethoxypropane and catalytic TsOH to afford a mixture of acetonides (17 as the major component and 18 as the minor component) as shown below, and its NOESY spectrum had cross peaks H-3/H-5, H-3, H-4/one of acetonide methyl groups in 17 and H-4′, H-5′/one of acetonide methyl groups in 18 (Scheme [2] ).

11

HPLC conditions: column: SHIMPACK ODS, 2 × 25 cm, Shimadzu; eluent: MeOH-CH₂Cl₂ (50:50); flow rate: 4 mL/min; t _R = 32 min.
Spectroscopic data of synthesized (-)-3: oil; [α]_D ²⁰ -98 (c 0.04, EtOH). IR (liquid film): 3366 (OH), 1725 (C=O), 1653 (C=C) cm^-1. ¹H NMR (acetone-d ₆): δ = 3.80 (3 H, s, COOMe), 4.07 (1 H, dd, J = 4.4, 1.9 Hz, H-4), 4.12 (1 H, dd, J = 4.6, 1.9 Hz, H-5), 4.38 (1 H, br dd, J = 4.4, 3.9 Hz, H-3), 4.90 (1 H, dd, J = 4.6, 0.8 Hz, H-6), 6.91 (d, J = 3.9 Hz, H-2). HRMS (EI): m/z calcd for C₈H₁₂O₅ ³⁵Cl [M + H]⁺: 223.0372; found: 223.0370.

12

HPLC conditions: same as above; t _R = 32 min. Specific rotation of natural (+)-3: [α]_D +104 (c, 0.04, EtOH).