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

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.

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

References

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<A NAME="RU08610ST-7">7</A>

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

Scheme 4

<A NAME="RU08610ST-8">8</A>

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

<A NAME="RU08610ST-9">9</A>

(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.

<A NAME="RU08610ST-10">10</A>

(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.

<A NAME="RU08610ST-11">11</A>

^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.

<A NAME="RU08610ST-12">12</A>

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.