Synthesis and structure of diastereomers of pentenocin B produced by Trichoderma hamatum FO-6903

Article abstract of DOI:10.1016/j.tetlet.2003.12.120

All diastereomers of pentenocin B, an inhibitor of interleukin-1β converting enzyme produced by Trichoderma hamatum FO-6903, were synthesized in chiral forms starting from L-threonine. Absolute configurations of natural pentenocin B were clarified to be 4S, 5R, and 6R.

Full text of DOI:10.1016/j.tetlet.2003.12.120

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1639–1641
Synthesis and structure of diastereomers of pentenocin B produced
by Trichoderma hamatum FO-6903
Susumu Ohira,* Hiroyuki Fujiwara, Kiyomi Maeda, Masaharu Habara, Naomi Sakaedani,
Megumi Akiyama and Atsuhito Kuboki
Department of Biological Chemistry, Faculty of Science, Okayama University of Science, 1-1 Ridai-cho, Okayama 700-0005, Japan
Received 21 November 2003; revised 17 December 2003; accepted 22 December 2003
Abstract—All diastereomers of pentenocin B, an inhibitor of interleukin-1b converting enzyme produced by Trichoderma hamatum
FO-6903, were synthesized in chiral forms starting from L-threonine. Absolute configurations of natural pentenocin B were clarified
to be 4S, 5R, and 6R.
Ó 2004 Elsevier Ltd. All rights reserved.
Pentenocin B, a weak inhibitor of interleukin-1b con-
verting enzyme, was isolated from the cultured broth of
Trichoderma hamatum FO-6903.1 The fundamental
structure was determined by spectroscopic analysis,
however, the relative and absolute stereochemistry of
three asymmetric centers was not known. Here, we
describe the synthesis of all possible diastereomers of
Reduction of methyl ester 6 with DIBAL followed by
Wittig reaction gave an a,b-unsaturated ketone, which
was hydrogenated to saturated ketone 7. Generation
of alkylidenecarbene using lithiotrimethylsilyldiazo-
methane5 afforded cyclopentene 8 in moderate yield via
C–H insertion reaction. Epoxidation of 8 with m-CPBA
provided a separable 3:2 mixture of epoxides 9 and 10.
The stereochemistry of 10 was deduced based on the
correlation between C-7 methyl protons and C-5 proton
of 10 in its NOESY spectra6 (Scheme 1).
pentenocin B (1, 2, 3, and 4) starting from L-threonine.
The result of the synthesis confirmed absolute configu-
rations of natural pentenocin B to be 4S, 5R, and 6R as
shown in 52 (Fig. 1).
Treatment of epoxide 9 with diethylaluminum 2,2,6,6-
tetramethylpiperidide7 at 0 °C cleanly furnished an
allylic alcohol that was protected as TBS ether 11. When
the other basic reagents like LDA-t-BuOK8 were used in
this transformation, the double bond regioisomer was
produced in some amount. Cleavage of the double bond
of 11 followed by oxidation of TBS enol ether of 12 with
palladium acetate9 gave a,b-unsaturated ketone 13.
Deprotection with trifluoroacetic acid cleanly delivered
The key step of the synthesis is the 1,5 C–H insertion
reaction of alkylidenecarbene generated from ketone to
construct the chiral quaternary center.3 Triol 1 and 2
were our first targets, because (4S)-trans-2,2,5-trimethyl-
4-(methoxycarbonyl)-1,3-dioxolane (6) is readily pre-
pared in a chiral form from L
-threonine.4
1
the final compound 1 although in low yield. The H
NMR spectra of 110 were quite different from those of
the natural product.
Epoxide 10, a possible intermediate for triol 2, could not
be cleaved to the allylic alcohol under various condi-
tions. All attempts to epimerize the allylic alcohol
obtained from 9 were also unsuccessful. Therefore,
acetoxymethyl group substituted cyclopentene 15
(Scheme 2) was prepared from ketone 14, which in turn
was derived from 6 using a different Wittig reagent.11
Dihydroxylation of 15 fortunately gave diol 16 as a
sole product with the desired stereochemistry that was
Figure 1.
Keywords: Pentenocin; C–H insertion; Alkylidenecarbene; L-threonine.
* Corresponding author. Tel./fax: +81-86-256-9425; e-mail: sohira@
dbc.ous.ac.jp
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.12.120

1640
S. Ohira et al. / Tetrahedron Letters 45 (2004) 1639–1641
Scheme 3. Reagents and conditions: (a) DIBAL, CH2Cl2, )78 °C; (b)
Ph3P@CHCOCH3, benzene, 60 °C (84% in two steps); (c) H2, Pd/C,
EtOAc (86%); (d) TMSCHN2, BuLi, THF, )78ꢁ0 °C (70%); (e)
m-CPBA, NaHCO3, CH2Cl2, rt (76%); (f) LiTMP, Et2AlCl, toluene,
0 °C (79%, 67%); (g) TBSOTf, Et3N, CH2Cl2, rt (94%, 95%); (h) OsO4,
NMO, THF–H2O, rt; (i) NaIO4, THF–H2O, rt (each 88% in two
steps); (j) TBSOTf, Et3N, CH2Cl2, rt (91%, 100%); (k) Pd(OAc)2,
CH3CN, rt (49%, 93%); (l) CF3COOH, 0 °C (27%, 54%).
Scheme 1. Reagents and conditions: (a) DIBAL, CH2Cl2, )78 °C; (b)
Ph3P@CHCOCH3, benzene, 60 °C (72% in two steps); (c) H2, PtO2,
EtOAc (81%); (d) TMSCHN2, BuLi, THF, )78ꢁ0 °C (42%); (e)
m-CPBA, NaHCO3, CH2Cl2, rt (77%); (f) LiTMP, Et2AlCl, toluene
0 °C (90%); (g) TBSOTf, Et3N, CH2Cl2, rt (96%); (h) OsO4, NMO,
THF–H2O, rt (100%); (i) NaIO4, THF–H2O, rt (96%); (j) TBSOTf,
Et3N, CH2Cl2, rt (98%); (k) Pd(OAc)2, CH3CN, rt (57%); (l)
CF3COOH, rt (10%).
Deacetylation under basic conditions induced the TBS
group transfer to the primary alcohol. Reductive
deacetylation with DIBAL and immediate glycol scis-
sion gave the desired product 19 from 17 and the
unreacted diol from 18. Stereochemistry of 16 was now
1
distinct because H NMR spectra of 19 were different
from 12. Conversion of ketone 19 to triol 2 was achieved
in three steps in a similar manner as the synthesis of triol
1. 1H NMR spectra of 210 were also different from those
of the natural product.
disclosed at a later stage. Treatment of 16 with TBSOTf
and triethylamine afforded an inseparable mixture of
mono-silylated minor product 17 and major product 18.
Synthesis of 3 and 4 was started from (4S)-cis-2,2,5-
trimethyl-4-(methoxycarbonyl)-1,3-dioxolane (20) that
was practically available from
L
-threonine by IbukaÕs
method.12 Ester 20 was transformed to epoxides 21 and
22 in a similar way as the synthesis of 1. Stereochemistry
of epoxide 22 (mp 52–56 °C) was confirmed by X-ray
structure analysis13 (Scheme 3).
Both epoxides could be cleaved to allylic alcohols and
were converted into triols 310 and 410 similarly to the
synthesis of 1. Spectral properties of 4 were identical
with those of the natural product, and the sign of optical
rotation (½aꢀ )58° (c 0.40, H2O)) was opposite to that
D
of the natural product (½aꢀ +76° (c 1.0, H2O)).14 Thus,
D
natural pentenocin B is the enantiomer of 4. Namely,
absolute configurations of natural pentenocin B are 4S,
5R, 6R, as shown in 5.
Acknowledgements
Scheme 2. Reagents and conditions: (a) DIBAL, CH2Cl2, )78 °C; (b)
Ph3P@CHCOCH2Ac, benzene, 60 °C (71% in two steps); (c) H2, Pd/C,
EtOAc (92%); (d) TMSCHN2, BuLi, THF, )78ꢁ0 °C (33%); (e) OsO4,
NMO, THF–H2O, rt (52%); (f) TBSOTf, Et3N, CH2Cl2, 0 °C (81%);
(g) DIBAL, CH2Cl2, )78 °C (58%); (h) NaIO4, THF–H2O, rt (27%); (i)
TBSOTf, Et3N, CH2Cl2, rt (99%); (j) Pd(OAc)2, CH3CN, rt (66%); (k)
CF3COOH, rt (55%).
We thank Professor Satoshi Omura, Kitasato Institute,
1
for providing us with H and 13C NMR spectra as well
as information on the optical rotation. We also thank
Professor Hiroshi Nozaki, Okayama University of Sci-
ence, for X-ray analysis of the epoxide 22.

S. Ohira et al. / Tetrahedron Letters 45 (2004) 1639–1641
1641
1H, J ¼ 6:6 Hz), 4.31 (t, 1H, J ¼ 6:5 Hz), 5.29 (t, 1H,
J ¼ 6:6 Hz), 5.61 (s, 1H), 6.29 (d, 1H, J ¼ 6:4 Hz), 7.26 (d,
1H, J ¼ 6:4 Hz); 13C NMR (DMSO-d6) d 19.43, 69.13,
83.62, 84.11, 133.72, 160.34, 204.35.
References and notes
1. (a) Matsumoto, T.; Ishiyama, A.; Yamaguchi, Y.;
Masuma, R.; Ui, H.; Shiomi, K.; Yamada, H.; Omura, S.
J. Antibiot. 1999, 52, 754–757; (b) Matsumoto, T.;
Ishiyama, A.; Yamaguchi, Y.; Masuma, R.; Ui, H.; Shiomi,
K.; Yamada, H.; Omura, S. J. Antibiot. 2003, 56, C2.
2. While this manuscript was in preparation, another group
reported determination of the absolute structure of pent-
enocin B by synthesis of all racemic diastereomers and the
natural type enantiomer. The structure they suggested was
identical to ours, Sugahara, T.; Fukuda, H.; Iwabuchi, Y.
Tennen Yuki Kagobutsu Toronkai Koen Yoshishu 2003, 45,
573–578.
2: ½aꢀ )89° (c 0.42, MeOH); 1H NMR (DMSO-d6) d 1.15
D
(d, 3H, J ¼ 6:4 Hz), 3.66 (quint, 1H, J ¼ 6:4 Hz), 3.91 (d,
1H, J ¼ 7:2 Hz), 4.84 (s, 1H), 4.86 (d, 1H, J ¼ 6:4 Hz),
5.47 (d, 1H, J ¼ 7:2 Hz), 6.22 (d, 1H, J ¼ 6:2 Hz), 7.60 (d,
1H, J ¼ 6:2 Hz); 13C NMR (DMSO-d6) d 18.90, 69.99,
73.94, 80.33, 134.19, 163.48, 208.84.
1
3: ½aꢀ )117° (c 0.12, H2O); H NMR (DMSO-d6) d 0.80
D
(d, 3H, J ¼ 6:4 Hz), 3.79 (quint, 1H, J ¼ 6:4 Hz), 4.05 (d,
1H, J ¼ 5:5 Hz), 4.63 (d, 1H, J ¼ 6:4 Hz), 5.38 (s, 1H),
5.90 (d, 1H, J ¼ 5:5 Hz), 6.30 (d, 1H, J ¼ 6:3 Hz), 7.31 (d,
1H, J ¼ 6:3 Hz); 13C NMR (DMSO-d6) d 19.60, 70.86,
82.60, 83.71, 132.80, 162.72, 205.40.
3. (a) Ohira, S.; Ida, T.; Moritani, M.; Hasegawa, T.
J. Chem. Soc., Perkin Trans. 1 1998, 293–298; (b) Ohira, S.;
Noda, I.; Mizobata, T.; Yamato, M. Tetrahedron Lett.
1995, 36, 3375–3376.
4: ½aꢀ )58° (c 0.40, H2O); 1H NMR (DMSO-d6) d 1.13 (d,
D
3H, J ¼ 6:4 Hz), 3.70 (qd, 1H, J ¼ 5:4 Hz, 6.4 Hz), 3.92 (d,
1H, J ¼ 7:5 Hz), 4.80 (d, 1H, J ¼ 5:4 Hz), 4.86 (s, 1H),
5.31 (d, 1H, J ¼ 7:5 Hz), 6.16 (d, 1H, J ¼ 6:2 Hz), 7.49 (d,
1H, J ¼ 6:2 Hz); 13C NMR (DMSO-d6) d 19.19, 70.52,
72.02, 80.08, 133.03, 166.68, 209.51.
4. Servi, S. J. Org. Chem. 1985, 50, 5865–5867.
5. (a) Sakai, A.; Aoyama, T.; Shioiri, T. Tetrahedron Lett.
2000, 41, 6859–6863; (b) Shioiri, T.; Aoyama, T. Synth.
Org. Chem., Jpn. 1996, 54, 918–928; (c) Ohira, S.; Okai, K.;
Moritani, T. J. Chem. Soc., Chem. Commun. 1992, 721–722.
6. 1H NMR (CDCl3) d 1.27 (d, 3H, J ¼ 6:3 Hz), 1.38 (s, 3H),
1.45 (s, 3H), 1.52 (s, 3H), 1.54 (m, 2H), 1.96 (m, 2H), 3.19
(s, 1H), 4.01 (q, 1H, J ¼ 6:3 Hz). Correlation was observed
between signals of d 1.27 and d 3.19.
7. Yasuda, A.; Tanaka, S.; Oshima, K.; Yamamoto, H.;
Nozaki, H. J. Am. Chem. Soc. 1974, 96, 6513–6514.
8. Mordini, A.; Ben Rayana, E.; Margot, C.; Schlosser, M.
Tetrahedron 1990, 46, 2401–2410.
11. Kim, K. S.; Szarek, W. A. Can. J. Chem. 1981, 59, 878–
888.
12. Ibuka, T.; Nishii, S.; Yamamoto, Y. Chem. Express 1988,
3, 53–56.
13. Suitable crystals of 22 for X-ray diffraction studies formed
with space group symmetry of P1 (#1) and cell constants
ꢀ
ꢀ
ꢀ
of a ¼ 7:465ð5Þ A, b ¼ 7:480ð4Þ A, c ¼ 9:781ð5Þ A for
Z ¼ 2 and calculated density of 1.246 g/cm3. Details will
be reported in due course.
14. Private communication from Professor Satoshi Omura.
Higher value (½aꢀ +101° (c 1.0, H2O)) was reported for
9. Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43,
1011–1013, We used a stoichiometric amount of palladium
acetate without benzoquinone to avoid the production of
dihydrobenzoquinone, which caused a problem in material
purification.
D
synthetic (+)-pentenocine B.2 To check the enatiomeric
1
purity of our samples, we examined H NMR spectra of
(S)-MTPA ester of the allylic alcohol from 22. No signal
for the diastereomer originating from the enantiomer of 22
was observed.
10. 1: ½aꢀ )53° (c 0.16, MeOH); 1H NMR (DMSO-d6) d 1.10
D
(d, 3H, J ¼ 6:5 Hz), 3.81 (quint, 1H, J ¼ 6:5 Hz), 3.90 (d,