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Synlett 2010(19): 2944-2946  
DOI: 10.1055/s-0030-1259045
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

First Stereoselective Synthesis of Penicillenol A1 via Novel O- to C-Acyl Rearrangement of O-Acyltetramic Acid

Tetsuya Sengoku, Jolanta Wierzejska, Masaki Takahashi, Hidemi Yoda*
Department of Materials Science, Faculty of Engineering, Shizuoka University, 3-5-1 Johoku, Naka-ku, Hamamatsu, Shizuoka 432-8561, Japan
Fax: +81(53)4781150; e-Mail: tchyoda@ipc.shizuoka.ac.jp;
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Publication History

Received 28 September 2010
Publication Date:
11 November 2010 (online)

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Abstract

The first stereoselective synthesis of penicillenol A1 has been accomplished in nine steps from l-threonine. The 3-acyltetramic acid core of penicillenol A1 was constructed by successful O- to C-acyl rearrangement.

Key words

stereoselective synthesis - penicillenol A1 - acyl rearrangement - 4-O-acyltetramic acid - 3-acyltetramic acid

    References

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7

Under the same conditions, one-pot acylation between 3 and hexanoic acid gave 3-acyltetramic acid in 64% yield (Scheme  [4] ).

Scheme 4

8

The addition of CaCl2 also improved the yield in a one-pot procedure. For example, the reaction of 3 with (R)-4 in the presence of CaCl2 afforded (6R,9R)-6 in 59% yield (Scheme  [5] ), whereas a trace amount of (6R,9R)-6 was obtained in the absence of CaCl2 (see Scheme  [³] ).

Scheme 5

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(6 R ,9 R )-Penicillenol A 1 [(6 R ,9 R )-1]
[α]D ²6 -30.5 (c 0.276, MeOH). IR (NaCl): 3414, 2956, 2927, 2857, 1709, 1642, 1611, 1484, 1462, 1379, 1342, 1089 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 4.19 (dq, J = 4.6, 6.4 Hz, 1 H, CH), 3.81 (d, J = 4.6 Hz, 1 H, CH), 3.56 (m, 1 H, CH), 2.98 (s, 3 H, CH3), 1.68 (m, 1 H, CH2), 1.49 (m, 1 H, CH2),1.33-1.21 (m, 8 H, CH2), 1.18 (d, J = 7.0 Hz, 3 H, CH3), 1.13 (d, J = 6.4 Hz, 3 H, CH3), 0.86 (t, J = 6.8 Hz, 3 H, CH3). ¹³C NMR (75 MHz, CDCl3): δ = 195.0 (C), 192.9 (C), 174.1 (C), 101.3 (C), 68.4 (CH), 66.6 (CH), 36.3 (CH), 33.9 (CH2), 31.7 (CH2), 29.1 (CH2), 27.1 (CH3), 27.0 (CH2), 22.5 (CH2), 17.5 (CH3), 17.1 (CH3), 14.0 (CH3). Anal. Calcd for C16H27NO4: C, 64.62; H, 9.15; N, 4.71. Found: C, 64.55; H, 9.08; N, 4.31.

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(6 R ,9 S )-Penicillenol A 1 [(6 R ,9 S )-1]
[α]D ²9 -68.5 (c 0.618, MeOH). IR (NaCl): 3425, 2956, 2928, 2857, 1708, 1642, 1610, 1486, 1460, 1378, 1342, 1089 cm-¹. ¹H NMR (300 MHz, CDCl3): δ = 4.19 (dq, J = 4.2, 6.3 Hz, 1 H, CH), 3.80 (d, J = 4.2 Hz, 1 H, CH), 3.56 (m, 1 H, CH), 2.99 (s, 3 H, CH3), 1.68 (m, 1 H, CH2), 1.47 (m, 1 H, CH2),1.33-1.22 (m, 8 H, CH2), 1.18 (d, J = 6.9 Hz, 3 H, CH3), 1.14 (d, J = 6.6 Hz, 3 H, CH3), 0.87 (t, J = 6.6 Hz, 3 H, CH3). ¹³C NMR (75 MHz, CDCl3): δ = 194.7 (C), 192.8 (C), 174.1 (C), 100.9 (C), 68.5 (CH), 66.6 (CH), 36.4 (CH), 33.4 (CH2), 31.5 (CH2), 29.1 (CH2), 27.1 (CH3), 27.0 (CH2), 22.4 (CH2), 17.6 (CH3), 17.0 (CH3), 13.9 (CH3). Anal. Calcd for C16H27NO4: C, 64.62; H, 9.15; N, 4.71. Found: C, 64.86; H, 9.00; N, 4.31.

11

¹H NMR and ¹³C NMR spectra of 5R isomer of (6R,9R)-1, which was prepared by isomerization of 3 (DBU, toluene,
50 ˚C), was found to be quite similar to those of natural penicillenol A2. This indicated that enantiomeric 5S,6S isomers should give NMR spectra similar to those of penicillenol A2. Details of synthesis and characterization of 5R isomer of (6R,9R)-1 will be presented in future work.

12

Synthetic sample was obtained as a colorless oil after separation from orange-colored material by silica gel column chromatography. Due to the fact that the natural sample has been reported to be isolated as an yellow oil, we conclude that the previously reported value of optical rotation was obtained by measuring incompletely purified one.