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.

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

References and Notes

<A NAME="RU02506ST-1">1</A> Numata A. Iritani M. Yamada T. Minoura K. Matsumura E. Yamori T. Tsuruo T. Tetrahedron Lett.  1997,  38:  8215 

<A NAME="RU02506ST-2">2</A> Usami Y. Numata A. Synlett  1999,  723 

<A NAME="RU02506ST-3">3</A> Usami Y. Ikura T. Amagata T. Numata A. Tetrahedron: Asymmetry  2000,  11:  3711 

<A NAME="RU02506ST-4">4</A> Usami Y. Numata A. Chem. Pharm. Bull.  2004,  52:  1125 

<A NAME="RU02506ST-5A">5a</A> Usami Y. Hatsuno C. Yamamoto H. Tanabe M. Numata A. Chem. Pharm. Bull.  2004,  52:  1130 

<A NAME="RU02506ST-5B">5b</A> Usami Y. Hatsuno C. Yamamoto H. Tanabe M. Numata A. Chem. Pharm. Bull.  2005,  53:  271 

For reviews, see:

<A NAME="RU02506ST-6A">6a</A> Suami T. Pure Appl. Chem.  1987,  59:  1509 

<A NAME="RU02506ST-6B">6b</A> Suami T. Ogawa S. Adv. Carbohydr. Chem. Biochem.  1990,  48:  21 

<A NAME="RU02506ST-6C">6c</A> Suami T. Top. Curr. Chem.  1990,  154:  257 

<A NAME="RU02506ST-6D">6d</A> Berecibar A. Grandjean C. Sinwardena A. Chem. Rev.  1999,  99:  779 

<A NAME="RU02506ST-7">7</A> Usami Y. Ueda Y. Chem. Lett.  2005,  34:  1062 

<A NAME="RU02506ST-8">8</A> Barco A. Benetti S. Risi CD. Marchetti P. Pollini GP. Zanirato V. Tetrahedron: Asymmetry  1997,  8:  3515 

<A NAME="RU02506ST-9">9</A> Ulibarri G. Nadler W. Skrydstrup T. Audrain H. Chianori A. Riche C. Grierson AA. J. Org. Chem.  1995,  60:  2753 

<A NAME="RU02506ST-10">10</A>

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] ).

<A NAME="RU02506ST-11">11</A>

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.

<A NAME="RU02506ST-12">12</A>

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