Synthesis of kuehneromycin B and panudial from kuehneromycin A

Article abstract of DOI:10.1055/s-2004-815966

Syntheses of kuehneromycin B and panudial are presented starting from kuehneromycin A using a thermal decarboxylation under pH control.

Full text of DOI:10.1055/s-2004-815966

SHORT PAPER
665
Synthesis of Kuehneromycin B and Panudial from Kuehneromycin A
K
uehneromycin B
a
and
P
anu
r
dia
l
sten Wallner, Johann Jauch*1
Institut für Organische Chemie und Biochemie der Technischen Universität München, Lichtenbergstrasse 4, 85747 Garching, Germany
E-mail: johann.jauch@ch.tum.de
Received 3 September 2003
Dedicated to Prof. Dr. W. Steglich on the occasion of his 70th birthday.
Our first plan was to start from an intermediate 4 of our
Abstract: Syntheses of kuehneromycin B and panudial are present-
synthesis of anhydromarasmone.5 Decarboxylation under
mild basic conditions (dilute NaOH solution) should lead
ed starting from kuehneromycin A using a thermal decarboxylation
under pH control.
to 5, which upon oxidation should give a mixture of 1 and
Key words: total synthesis, terpenoids, natural products, hydroly-
3 (Scheme 1).
sis, decarboxylation
Kuehneromycin B (1) (Figure 1), recently described by
Anke and Steglich,2 is a minor component found in
Kuehneromyces sp. 8758. Kuehneromycin B inhibits re-
verse transcriptase of HIV and other retrovirusses. Bio-
synthetically, kuehneromycin B is the decarboxylation
product of kuehneromycin A (2), which is a major compo-
nent, found in the same mushroom.2,3
Scheme 1 First synthetic approach to kuehneromycin B and panu-
dial.
Consumption of the starting material occurred smoothly
at 25 °C within 6 hours and two new compounds ap-
peared, as reaction monitoring revealed. Unfortunately,
during this reaction, the expected acyl-O-cleavage6 with
concomitant decarboxylation did not occur. Instead, we
found alkyl-O-cleavage7 exclusively, leading to the dias-
Figure 1 Relationship between kuehneromycin B (1), kuehneromy-
tereomerically pure8 carboxylic acid 6a and the corre-
cin A (2) and panudial (3).
sponding ethyl ester 6b (Scheme 2).
Since strong bases usually give alkyl-O-cleavage, in the
next experiment we used NaHCO3 as base and DMSO as
solvent to inhibit ester formation. Unfortunately, under
these conditions, 4 also gave alkyl-O-cleavage leading
only to 6a.
Panudial (3) (Figure 1), a stereoisomer of kuehneromycin
B is found in Panus species (strain 9096) and inhibits
platelet aggregation.4 Whereas the biosynthetic precursor
of panudial is unknown, Steglich et al. demonstrated the
interconversion of kuehneromycin B into panudial and
vice versa on treatment with DBU.2
Therefore, we switched to kuehneromycin A (2) as the
starting material and studied direct decarboxylation reac-
tions under neutral conditions according to Figure 1.
Here, we wish to report our studies on the decarboxylation
of kuehneromycin A (2) leading to kuehneromycin B (1)
and panudial (3).
Heating a small sample of kuehneromycin A in D2O–ace-
tone-d6 to 120 °C for 10 minutes gave a mixture of kueh-
neromycin B and panudial (approximately 1:1 as seen
from 1H NMR). For preparative purposes, we switched to
pH 7 buffer together with acetone as co-solvent to have a
defined reaction medium. Under these conditions, after 10
minutes at 120 °C we found a mixture of panudial (3) and
SYNTHESIS 2004, No. 5, pp 0665–0667
x
x
.
x
x
.2
0
0
4
Advanced online publication: 10.02.2004
DOI: 10.1055/s-2004-815966; Art ID: T09503SS
© Georg Thieme Verlag Stuttgart · New York

666
C. Wallner, J. Jauch
SHORT PAPER
Scheme 2 Attempted decarboxylation under basic conditions lea-
ding to alkyl-O-cleavage.
kuehneromycin B (1) (selectivity 9:1) (Scheme 3). The
two compounds could be readily separated via flash chro-
matography on reversed phase silica gel using MeOH–
water (9:1) as eluent.
In addition to this experiment, we further explored the pH
influence of the reaction medium on decarboxylation.
With pH 6 buffer–acetone as reaction medium after 10
minutes at 120 °C we obtained kuehneromycin B (1) as
main product with minor amounts of panudial (3)
(Scheme 3).
Figure 2 a) CD spectra from lit.2 reproduced with kind permission
of Zeitschrift für Naturforschung; b) CD spectra of synthetic kuehne-
romycin B (1) and panudial (3). For details see the experimental part.
in Figure 1 and both compounds are stereochemically re-
lated to kuehneromycin A.
Kuehneromycin A3 (2) and tetracycle5 (4) were synthesized as de-
scribed previously. All reactions were run without inert gas in
closed vials. Organic solvents were distilled prior to use. Reactions
were monitored on TLC plates (silica gel glass plates Si60 F254 and
RP18 F254s, Merck, Darmstadt). NMR spectra were recorded on
Bruker AV 360, AV 500 and AM 600 spectrometers. Mass spectra
were obtained in EI mode on a Finnigan MAT 8200. Optical rota-
tions were recorded on a Perkin Elmer Polarimeter MC 241. CD
spectra were obtained on a Jasco-J 715 spectropolarimeter with
PTC 343 peltier unit at 20 °C.
Scheme 3 Decarboxylation of kuehneromycin A (2) at different pH.
1
In all decarboxylation reactions the H NMR spectra
showed two additional diastereomers of 3 and 1 (together
less than 5%).
Lactones 6a and 6b; General Procedure
1
Whereas H and 13C NMR spectra of the synthetic com- Tetracycle 4 (19 mg, 72.5 mmol) was dissolved in EtOH (0.6 mL).
Aqueous 1 N NaOH (80 ml, 80 mol, 1.1 equiv) was added and the
reaction mixture was stirred at r.t. for 6 h (reaction was monitored
by TLC on silica gel plates with Et2O–pentane, 3:1). The reaction
was quenched with a mixture of cold 1 N HCl and sat. aq NH4Cl (10
mL, 1:1). Extraction with Et2O (5 × 10 mL) followed by drying
with MgSO4, filtration and evaporation of the solvent gave the
crude products, which were purified by preparative TLC (silica gel,
Et2O–pentane, 3:1).
pounds were identical to those obtained from natural
sources, we experienced some inconsistencies regarding
the specific rotations.
To reveal the reason for these inconsistencies we recorded
CD spectra of our synthetic compounds and compared the
data obtained with those published by Steglich et al.2
(Figure 2).
The CD spectra of isolated and synthetic kuehneromycin
B and panudial are identical.9 Therefore absolute config-
urations of kuehneromycin B and panudial are as depicted
6a
Yield: 8.4 mg (41%); [a]D20 –54 (c = 0.04, CDCl3).
1H NMR (360 MHz, CDCl3): d = 6.01 (d, J = 4.5 Hz, 1 H, H11),
5,98 (dt, J = 10.2, 2.7 Hz, 1 H, H6), 5.71 (dt, J = 10.2, 2.7 Hz, 1 H,
Synthesis 2004, No. 5, 665–667 © Thieme Stuttgart · New York

SHORT PAPER
Kuehneromycin B and Panudial
667
H7), 4.35 (t, J = 8.9 Hz, 1 H, H12), 3.66 (t, J = 8.9 Hz, 1 H, H12),
3.29–3.18 (m, 2 H, H9, H10), 2.83 (dddd, J = 19.3, 10.4, 8.9 Hz, 2.7
Hz, 1 H, H8), 2.37 (dd, J = 8.4, 8.2 Hz, 2 H, H3), 2.30 (m, 1 H, H5),
1.92–1.83 (m, 1 H, H2), 1.79–1.70 (m, 1 H, H2), 1.12 (s, 6 H, H13,
H14).
13C NMR (90.56 MHz): d = 178.8 (C1), 173.2 (C15), 128.9 (C6),
127.5 (C7), 105.6 (C11), 73.0 (C12), 45.6 (C9), 44.0 (C5), 41.0
(C10), 36.0 (C2), 34.3 (C4), 34.2 (C8), 29.3 (C3), 25.2 (C13), 24.4
(C14).
added and the mixture was heated in a closed vial at 120 °C for 10
min. After cooling to r.t., the reaction mixture was extracted with
CHCl3 (5 × 10 mL). The combined extracts were washed with
brine, dried with MgSO4, filtrated and evaporated to dryness in vac-
uo. The crude product was purified by preparative TLC (RP18 silica
gel, MeOH–H2O, 70:30); yield: 11.0 mg (82%).
1H NMR (360 MHz, CDCl3): d = 9.62 (s, 1 H, H11), 9.55 (s, 1 H,
H12), 6.94 (m, 1 H, H7), 4.11 (m, 1 H, H9), 3.68 (d, J = 4.8 Hz, 1
H, H10), 2.54 (td, J = 14.1, 7.0 Hz, 1 H, H2b), 2.50 (dt, J = 19.7, 5.0
Hz, 1 H, H6a), 2.28 (ddd, J = 14.5, 5.2, 2.0 Hz, 1 H, H2a), 2.01 (ddt,
J = 19.7, 11.8, 2.5 Hz, 1 H, H6b), 1.91 (dd, J = 5.0, 2.1 Hz, 1 H, H5),
1.90 (td, J = 14.1, 5.0 Hz, 1 H, H3a), 1.69 (ddt, J = 14.2, 7.2, 2.0 Hz,
1 H, H3b), 1.42 (s, 3 H, H14), 1.01 (s, 3 H, H13).
MS (EI, 80 °C): m/z (%) = 281 (6) [M +H ]+, 280 (1) [M+], 263 (10)
[M – OH]+, 262 (33) [M – H2O]+, 218 (8), 188 (42), 166 (95), 115
(100), 97 (99), 69 (84).
6b
13C NMR (90.56 MHz): d = 209.0 (C1), 199.2 (C11), 192.5 (C12),
151.5 (C7), 135.3 (C8), 44.7 (C9), 43.7 (C5), 42.6 (C10), 37.7 (C2),
35.2 (C3), 33.0 (C4), 27.7 (C13), 26.4 (C14), 26.1 (C6).
MS (EI, 80 °C): m/z = 234 (2) [M]+, 206 (100) [M – CO]+, 188 (12),
173 (10), 150 (24), 132 (81), 108 (20), 107 (56), 91 (28).
HRMS: m/z [M – CO]+ calcd for C13H18O2: 206.1307; found:
206.1305.
Yield: 10.7 mg (48%); [a]D20 +6 (c = 0.11, CDCl3).
1H NMR (360 MHz, CDCl3): d = 6.01 (d, J = 4.5 Hz, 1 H, H11),
5,98 (dt, J = 10.2, 2.7 Hz, 1 H, H6), 5.70 (dt, J = 10.2, 2.8 Hz, 1 H,
H7), 4.35 (t, J = 9.0 Hz, 1 H, H12), 4.12 (q, J = 7.1 Hz, 2 H, H1¢),
3.66 (t, J = 8.9 Hz, 1 H, H12), 3.28–3.17 (m, 2 H, H9, H10), 2.82
(dddd, J = 19.5, 9.1, 6.1, 2.7 Hz, 1 H, H8), 2.34–2.27 (m, 3 H, H3,
H5), 1.88–1.79 (m, 1 H, H2), 1.77–1.68 (m, 1 H, H2), 1.26 (t, J =
7.2 Hz, 3 H, H2¢), 1.11 (s, 6 H, H13, H14).
13C NMR (90.56 MHz): d = 174.1 (C1), 173.2 (C15), 129.1 (C6),
127.4 (C7), 105.6 (C11), 73.0 (C12), 60.4 (C1¢), 45.6 (C9), 43.9
(C5), 41.0 (C10), 36.4 (C2), 34.2 (C4), 34.1 (C8), 29.7 (C3), 25.2
(C13), 24.4 (C14), 14.2 (C2¢).
CD: (c = 0.4 mg/mL, CH3CN, 20 °C) lmax (De) = 206 (3.3), 216
(0.0), 229 (–4.3), 263 (–0.04), 310 (–0.3) nm.
Acknowledgment
This work was generously supported by the Deutsche Forschungs-
gemeinschaft. We thank Prof. Dr. W. Steglich, Ludwig-Maximili-
ans-Universität München, for copies of the NMR spectra of the
natural samples and for helpful discussions. We thank Thusnelda
Stromer, TU München, for CD spectra of our synthesized samples
and Dr. Haijun Jiao, Universität Rostock, for performing the DFT
calculations.
MS (EI, 80 °C): m/z (%) = 308 (2) [M+], 281 (79) [M – C2H3]+, 263
(14) [M – C2H5O]+, 262 (24), 232 (8), 188 (22), 166 (14), 143 (100),
97 (75), 69 (69).
Kuehneromycin B (1); Typical Procedure
Kuehneromycin A (2) (12.3 mg, 44 mol) was dissolved in acetone
(0.6 mL). A pH 6 buffer (Na2HPO4–KH2PO4–H2O, 4 mL)10 was
added and the mixture was heated in a closed vial at 120 °C for 10
min. After cooling to r.t., the reaction mixture was extracted with
CHCl3 (5 × 5 mL). The combined extracts were washed with brine,
dried with MgSO4, filtered and evaporated to dryness in vacuo. The
crude product was purified by preparative TLC (RP18 silica gel,
MeOH–H2O, 70:30); yield: 7.5 mg (72%).
References
(1) New address: Universität des Saarlandes, Organische
Chemie, Postfach 15 11 50, 66041 Saarbrücken, Germany.
E-mail: j.jauch@mx-uni-saarland.de.
(2) Erkel, G.; Lorenzen, K.; Anke, T.; Velten, R.; Gimenez, A.;
Steglich, W. Z. Naturforsch. C: Biosci. 1995, 50, 1.
(3) Jauch, J. Angew. Chem. Int. Ed. 2000, 39, 2764; Angew.
Chem. 2000, 112, 2874.
(4) Lorenzen, K.; Anke, T.; Anders, U.; Hindermayr, H.;
Hansske, F. Z. Naturforsch. C: Biosci. 1994, 49, 132.
(5) Jauch, J.; Wallner, C.; Herdtweck, E. Eur. J. Org. Chem.
2003, 3060.
(6) See e.g.: March, J. Advanced Organic Chemistry, 4th ed.;
Wiley: New York, 1992, 629; and literature cited therein.
(7) See e.g.: March, J. Advanced Organic Chemistry, 4th ed.;
Wiley: New York, 1992, 631.
(8) Under the assumption of thermodynamic control DFT
calculations (B3LYP/6-31G*) led to DDG(6a/10-epi-6a) of
ca. 8 kcal/mol. Thus, the equilibrium constant is ca. 106 in
favor of 6a.
1H NMR (600 MHz, CDCl3): d = 10.33 (d, J = 1.9 Hz, 1 H, H11),
9.35 (s, 1 H, H12), 6.99 (dt, J = 6.1, 2.2 Hz, 1 H, H7), 3.82 (ddddd,
J = 10.0, 3.9, 2.2, 2.0, 1.6 Hz, 1 H, H9), 2.87 (ddd, J = 12.8, 10.0,
1.2 Hz, 1 H, H10), 2.52 (ddd, J = 14.7, 8.0, 6.1 Hz, 1 H, H2b), 2.50
(ddd, J = 18.9, 6.1, 5.8 Hz, 1 H, H6a), 2.40 (ddd, J = 15.0, 4.2, 2.5
Hz, 1 H, H2a), 2.34 (dddd, J = 19.4, 11.4, 3.6, 2.5 Hz, 1 H, H6b),
1.80 (ddd, J = 13.7, 6.0, 2.5, 1 H, H3b), 1.65 (td, J = 12.7, 4.8 Hz,
1 H, H5), 1.63 (ddd, J = 13.6, 6.0, 4.8 Hz, 1 H, H3a), 1.15 (s, 3 H,
H14), 1.06 (s, 3 H, H13).
13C NMR (90.56 MHz): d = 208.9 (C1), 202.1 (C11), 192.3 (C12),
151.3 (C7), 140.7 (C8), 49.9 (C10), 46.3 (C9), 45.9 (C5), 40.8 (C3),
37.6 (C2), 32.8 (C4), 28.9 (C13), 27.9 (C6), 19.1 (C14).
MS (EI, 80 °C): m/z (%) = 234 (6) [M+], 206 (100) [M – CO]+, 188
(5), 173 (10), 150 (22), 132 (81), 108 (24), 107 (34).
HRMS: m/z [M – CO]+ calcd for C13H18O2: 206.1307; found:
206.1308.
(9) Unfortunately, the compounds have been mislabeled in the
CD spectra shown in Figure 2a. In the text of ref.2 the data of
the CD spectra have been listed correctly.
(10) CRC Handbook of Chemistry and Physics, 82nd ed.;
Chapman & Hall/CRC: New York, 2001.
CD: (c = 0.5 mg/mL, CH3CN, 20 °C) lmax (De) = 216 (–7.2), 231
(0.0), 243 (4.3), 266 (1.1), 288 (1.8) nm.
Panudial (3); Typical Procedure
Kuehneromycin A (2) (15.9 mg, 57 mol) was dissolved in acetone
(0.7 mL). A pH 7 buffer (Na2HPO4–KH2PO4–H2O, 4.6 mL)10 was
Synthesis 2004, No. 5, 665–667 © Thieme Stuttgart · New York