Total synthesis of (-)-pironetin

Article abstract of DOI:10.1021/ol027211o

(Matrix presented) The asymmetric total synthesis of pironetin, a compound that shows plant growth regulatory activity, immunosuppressive as well as a remarkable antitumoral activity, is described. The approach involves the use of three very efficient Eva

Full text of DOI:10.1021/ol027211o

ORGANIC
LETTERS
Total Synthesis of (−)-Pironetin†
2003
Vol. 5, No. 3
265-268
Luiz C. Dias,* Luciana G. de Oliveira, and Ma´rcio A. de Sousa
Instituto de Qu´ımica, UniVersidade Estadual de Campinas, UNICAMP,
C.P. 6154 13083-970, Campinas, SP, Brazil
ldias@iqm.unicamp.br
Received October 31, 2002
ABSTRACT
The asymmetric total synthesis of pironetin, a compound that shows plant growth regulatory activity, immunosuppressive as well as a remarkable
antitumoral activity, is described. The approach involves the use of three very efficient Evans oxazolidinone-mediated syn-aldol condensations,
a high-yielding coupling between lithium acetylide ethylenediamine complex and a tosylate followed by methylation, and selective reduction
to establish the C12−C13 (E) double bond.
Pironetin1 or PA-48153C2 (1) is an unsaturated δ-lactone
derivative, which was isolated independently by two research
groups from Streptomyces sp. NK10958 and from the
fermentation broths of Streptomyces prunicolor PA-48153,
respectively. This very interesting compound possesses plant
growth regulatory and immunosuppressive activities. Re-
cently, the biological effects of 1 and its derivatives on cell
cycle progression and antitumor activities were reported.3
More importantly, the mode of action of 1 is different from
those established for the immunosuppressants cyclosporin
A (CsA) and FK506 that inhibit T cell activation.4 Pironetin
showed suppressive effects on the responses of T and B
lymphocytes to mitogens.
The structure of pironetin has been suggested mainly by
spectral methods, the relative stereochemistry has been
determined by X-ray analysis, and the absolute configuration
has been confirmed by total synthesis.5,6 In a recent paper,
Osada et al. showed that the R,â-unsaturated lactone, the
chirality at the C7-position bearing a hydroxyl group, and
the terminal portion of the alkyl chain are important for
microtubule inhibitory activity of pironetins.3,6h To provide
material for more extensive biological evaluation, and to
develop a synthetic strategy useful for the preparation of
promising new derivatives of pironetin, we have undertaken
its total synthesis.
The illustrated structural examination of 1 revealed that
all syn stereocenters are present in pairs represented by C4-
C5, C7-C8, and C9-C10 units (Scheme 1).7 For introduc-
tion of these stereochemical centers, we explored three Evans
* Address correspondence to this author. FAX: +55-019-3788-3023.
† This paper is dedicated to Prof. Albert Kascheres on the occasion of
his 60th birthday and also to the Brazilian Chemical Society (SBQ).
(1) (a) Kobayashi, S.; Tsuchiya, K.; Harada, T.; Nishide, M.; Kurokawa,
T.; Nakagawa, T.; Shimada, N.; Kobayashi, K. J. Antibiot. 1994, 47, 697.
(b) Kobayashi, S.; Tsuchiya, K.; Kurokawa, T.; Nakagawa, T.; Shimada,
N.; Iitaka, Y. J. Antibiot. 1994, 47, 703. (c) Tsuchiya, K.; Kobayashi, S.;
Harada, T.; Nishikiori, T.; Nakagawa, T.; Tatsuta, K. J. Antibiot. 1997, 50,
259.
(2) (a) Yoshida, T.; Koizumi, K.; Kawamura, Y.; Matsumoto, K.; Itazaki,
H. Japan Patent Kokai 5-310726, 1993. (b) Yoshida, T.; Koizumi, K.;
Kawamura, Y.; Matsumoto, K.; Itazaki, H. European Patent 560389 A1,
1993. (c) Yasui, K.; Tamura, Y.; Nakatani, T.; Kawada, K.; Ohtani, M. J.
Org. Chem. 1995, 60, 7567.
(5) For biosyntetic studies on pironetin, see: Kobayashi, S.; Tsuchiya,
K.; Nishide, M.; Nishikiori, T.; Nakagawa, T.; Shimada, N. J. Antibiot.
1995, 48, 893.
(6) Total synthesis of pironetin and analogues: (a) References 2c and 4.
(b) Gurjar, M. K.; Henri, J. T., Jr.; Bose, D. S.; Rama Rao, A. V.
Tetrahedron Lett. 1996, 37, 6615. (c) Gurjar, M. K.; Chakrabarti, A.; Rama
Rao, A. V. Heterocycles 1997, 45, 7. (d) Chida, N.; Yoshinaga, M.; Tobe,
T.; Ogawa, S. Chem. Commun. 1997, 1043. (e) Watanabe, H.; Watanabe,
H.; Kitahara, T. Tetrahedron Lett. 1998, 39, 8313. (f) Kitahara, T.;
Watanabe, H. J. Synth. Org. Chem., Jpn. 1998, 56, 884. (g) Watanabe, H.;
Watanabe, H.; Bando, M.; Kido, M.; Kitahara, T. Tetrahedron 1999, 55,
9755. (h) Watanabe, H.; Watanabe, H.; Usui, T.; Kondoh, M.; Osada, H.;
Kitahara, T. J. Antibiot. 2000, 53, 540. (i) Keck, G. E.; Knutson, C. E.;
Wiles, S. A. Org. Lett. 2001, 3, 707.
(3) Kondoh, M.; Usui, T.; Kobayashi, S.; Tsuchiya, K.; Nishikawa, K.;
Nishikiori, T.; Mayumi, T.; Osada, H. Cancer Lett. 1998, 126, 29.
(4) For a paper about chemical modifications of pironetin to reduce its
toxicity, see: Yasui, K.; Tamura, Y.; Nakatani, T.; Horibe, I.; Kawada, K.;
Koizumi, K.; Suzuki, R.; Ohtani, M. J. Antibiot. 1996, 49, 173.
(7) The numbering of 1 follows that suggested in ref 1b.
10.1021/ol027211o CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/09/2003

Scheme 1
Scheme 2
ylhydroxylamine generated the Weinreb amide, purification
of which was done by isolation of the recyclable oxazoli-
dinone chiral auxiliary (92%) by efficient crystallization of
this oxazolidinone from the reaction mixture.11 Protection
of the OH-function as its TBS ether gave Weinreb amide
(+)-9 in 81% yield (over two steps, transamidation and TBS
protection). This amide was smoothly reduced to aldehyde
(+)-6 in 92% yield on treatment with diisobutylaluminum
hydride in toluene at 0 °C (Scheme 2). The aldehyde (+)-6,
without purification, was treated with the boron enolate
generated from (R)-oxazolidinone (-)-5 to give the corre-
sponding aldol adduct 10, which possesses the syn-anti-
syn stereochemistry concerning the four contiguous stereo-
centers, in 84% isolated yield and >95:5 diastereoselectivity
(Scheme 3).9 This result illustrates that the chiral auxiliary
asymmetric aldol reactions. By employing an aldol addition
of oxazolidinone 2 to aldehyde 3, we planned to establish
the stereocenters at C4 and C5. Aldehyde 3 may be further
dissected in a straightforward manner to give tosylate 4,
bearing 4 stereogenic centers. The C12-C13 (E) double bond
segment in 3 was viewed as arising from coupling between
lithium acetylide ethylenediamine complex and tosylate 4,
followed by methylation and selective reduction. Of the
available options for the synthesis of 4, we speculate that
the desired C8-C10 anti-methyl bearing stereocenters might
be established through a boron enolate mediated aldol
reaction using N-propionyloxazolidinone 5 with aldehyde 6,
with anti-Felkin addition, followed by methylation of the
newly formed OH-function.
Scheme 3
Synthesis of aldehyde 6 began with the known (S)-
acyloxazolidinone (+)-5, which was most conveniently
prepared by acylation of the correponding (-)-(S)-oxazoli-
dinone (Scheme 2).8
Asymmetric aldol addition of the boron enolate derived
from oxazolidinone (+)-5 with aldehyde 7 gave aldol adduct
(+)-8 in 87% isolated yield and with excellent diastereo-
selectivity (>95:5) (Scheme 2).9,10 Exchange of the oxazo-
lidinone auxiliary in the syn-aldol (+)-8 with N,O-dimeth-
(8) Evans, D. A.; Gage, J. R. Org. Synth. 1989, 68, 83.
(9) (a) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981,
103, 2127. (b) Evans, D. A.; Ng, H. P.; Clark, J. S.; Rieger, D. L.
Tetrahedron 1992, 48, 2127.
(10) Aldehyde 7 was prepared from 1,3-propanediol:
is effective in controlling the stereoselectivity of the reaction,
even overriding the facial bias of chiral aldehyde (+)-6 for
Felkin addition. Reductive removal of the oxazolidinone
266
Org. Lett., Vol. 5, No. 3, 2003

auxiliary in the crude aldol adduct 10 was accomplished with
LiBH4 in THF/MeOH at 0 °C.12 This protocol provided 1,3-
diol (+)-11 in 89% yield (Scheme 3). Recovery of the
oxazolidinone auxiliary in this reaction is nearly quantitative.
Selective tosylation of the primary OH-function led to
compound (+)-12 in 95% yield. Methylation with Me3OBF4
in the presence of a proton sponge at room temperature
proceeded smoothly, producing the desired product 4 in 89%
isolated yield (Scheme 3).13 Transformation of the aldol
adduct 10 to the corresponding lactone (+)-14 enabled the
relative stereochemistry of both aldol bond constructions to
be confirmed (Scheme 4). Treatment of aldol 10 with HF/
tosylate 4. We were gratified to see that this modification
proved successful (Scheme 5). The optimal conditions
Scheme 5
Scheme 4
involved treatment of tosylate 4 with 5 equiv of lithium
acetylide in DMSO at room temperature to give the acetylene
15.15 Treatment of 15 with n-BuLi and quenching with
methyl iodide gave the corresponding alkyne.16
Reduction of the alkyne proceeded smoothly providing
control for the E-geometry of the C12-C13 double bond
with concomitant removal of the PMB group at C5, giving
primary alcohol 16 in 49% yield for the three-step sequence
from 4.17 Swern oxidation of 16 under the standard conditions
gave the desired aldehyde in 94% yield (Scheme 5).18 A final
Evans-type asymmetric aldol reaction between the unpurified
aldehyde and the boron enolate derived from 28 proceeded
with high diastereoselectivity (>95:5) to give adduct 17 in
90% yield. At this juncture, all the stereocenters in the target
had been installed, leaving only final refunctionalizations to
complete the synthesis. The final steps of the synthesis are
summarized in Scheme 6. Protection of the secondary alcohol
functionality at C5 in 17 as its TBS ether followed by
reductive removal of the chiral auxiliary with LiBH4 in THF/
MeOH at 0 °C produced primary alcohol 18 in 87% overall
yield, along with almost quantitative recovery of the chiral
auxiliary.12 TPAP oxidation of 18 gave an intermediate
aldehyde that was directly submitted to a Horner-
Wadsworth-Emmons homologation with the requisite sta-
bilized reagent 19 under Ando’s conditions to give the
corresponding R,â-unsaturated ester 20 (Z:E >95:5) in 84%
yield (two steps).19,20
H2O/CH3CN to remove the TBS protecting group followed
by oxidative cleavage of the oxazolidinone auxiliary with
H2O2/LiOH14 gave an intermediate carboxylic acid (13, 70%
yield, two steps), which was dehydrated in refluxing benzene
to give lactone (+)-14 in 80% isolated yield. The observed
relative stereochemistry was proved by analysis of the
1
coupling constants in the H NMR spectrum as well as by
NOESY experiments. The illustrated NOESY interactions
on the lactone established the anti relationship between the
newly formed hydroxyl and methyl bearing stereocenter in
the anti-Felkin adduct 10. The large vicinal coupling constant
between H1-H2 (10.3 Hz), together with the small observed
values between H2-H3 (4.4 Hz) and H3-H4 (4.6 Hz),
unambiguously established the proposed syn-anti-syn rela-
tive stereochemistry of aldol adduct 10 (Scheme 4).
After examining several different attempts to couple C12
vinyl cuprates and C11 tosylates, bromides, and iodides, we
turned our attention to the use of a coupling approach
employing lithium acetylide ethylenediamine complex with
(11) Levin, J. I.; Turos, E.; Weinreb, S. Synth. Commun. 1982, 12, 989.
(12) Barnett, C. J.; Wilson, T. M.; Evans, D. A.; Somers, T. C.
Tetrahedron Lett. 1997, 38, 735.
(13) Evans, D. A.; Ratz, A. M.; Huff, B. E.; Sheppard, G. S. J. Am.
Chem. Soc. 1995, 117, 3448.
(15) (a) Toshima, K.; Jyojima, T.; Miyamoto, N.; Katohno, M.; Nakata,
M.; Matsumura, S. J. Org. Chem. 2001, 66, 1708. (b) Moune´, S.; Niel, G.;
Busquet, M.; Eggleston, I.; Jouin, P. J. Org. Chem. 1997, 62, 3332. (c)
Smith, N.; Beumel, O. F. Synthesis 1974, 441.
(14) Evans, D. A.; Britton, T. C.; Ellman, J. A. Tetrahedron Lett. 1987,
28, 6141.
(16) Buck, M.; Chong, J, M. Tetrahedron Lett. 2001, 42, 5825.
(17) Schon, I. Chem. ReV. 1984, 84, 287.
Org. Lett., Vol. 5, No. 3, 2003
267

[R]20D, Rf] were identical in all respects with the published
data.1-3,6 The synthesis required 18 steps from (+)-5 (longest
linear sequence), produced the desired product in 11% overall
yield, being amenable to a gram scale-up, and compares well
with other published routes,5,6 being one of the shortest
approaches.
Scheme 6
We described here an asymmetric total synthesis of
pironetin. Notable features of this approach include three
high-yielding syn aldol reactions to set up the six stereogenic
centers, a very efficient coupling between a tosylate and
lithium acetylide, followed by methylation and reduction to
establish the (E) double bond at C12-C13, and a dia-
stereoselective Horner-Wadsworth-Emmons reaction under
Ando’s conditions. The route to (-)-pironetin described here
might easily afford access to additional analogues with
potential relevance to biological studies. The results will be
described in a full account of this work.21
Acknowledgment. We are grateful to FAPESP (Funda-
c¸a˜o de Amparo a` Pesquisa do Estado de Sa˜o Paulo) and
CNPq (Conselho Nacional de Desenvolvimento Cient´ıfico
e Tecnolo´gico) for financial support. We thank also Prof.
Carol H. Collins for helpful suggestions about English
grammar and style and Dr. Ricardo M. Ellensohn for helpful
discussions and suggestions.
All that remained was to carry out the necessary lacton-
ization. Treatment of ester 20 with 1% HCl/EtOH at room
temperature occurred with efficient removal of both TBS
protecting groups positioned at C5 and C7, followed by
lactonization to give (-)-pironetin 1 in 89% isolated yield,
after purification by silica gel column chromatography.1,2,21
The spectroscopic and physical data [1H and 13C NMR, IR,
Supporting Information Available: Spectral data for key
intermediates and spectroscopic data for natural and synthetic
pironetin (1). This material is available free of charge via
the Internet at http://pubs.acs.org.
(18) Mancuso, A. J.; Swern, D. Synthesis 1981, 165.
(19) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis
1994, 639-666. (b) Bloch, R.; Brillet, C. Synlett 1991, 829-830.
(20) (a) Ando, K. J. Org. Chem. 1997, 62, 1934. (b) Ando, K. J. Org.
Chem. 1998, 63, 8411. (c) Ando, K. J. Org. Chem. 1999, 64, 8406. (d)
Ando, K.; Oishi, T.; Hirama, M.; Ohno, H.; Ibuka, T. J. Org. Chem. 2000,
65, 4745.
OL027211O
(21) New compounds and the additional isolated intermediates gave
satisfactory 1H and 13C NMR, IR, HRMS, and analytical data. Yields refer
to chromatographically and spectroscopically homogeneous materials.
268
Org. Lett., Vol. 5, No. 3, 2003