Enantioselective total synthesis of pteridic acid A

Article abstract of DOI:10.1039/b416309e

Pteridic acid A, a potent plant growth promoter with auxin-like activity, was synthesized enantioselectively by using the Evans asymmetric aldol reaction as the key C-C bond forming step. The Royal Society of Chemistry 2005.

Full text of DOI:10.1039/b416309e

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Enantioselective total synthesis of pteridic acid A{
Takashi Nakahata and Shigefumi Kuwahara*
Received (in Cambridge, UK) 25th October 2004, Accepted 23rd November 2004
First published as an Advance Article on the web 5th January 2005
DOI: 10.1039/b416309e
produced a 13:1 mixture of 6a and its (7a,8a)-diastereomer
Pteridic acid A, a potent plant growth promoter with auxin-like
activity, was synthesized enantioselectively by using the Evans
asymmetric aldol reaction as the key C–C bond forming step.
favoring the desired 8,10-anti-adduct (6a). The mixture was
subjected to a three-step sequence consisting of stereoselective
reduction to 6b (stereoselectivity, 10:1),5 conversion to acetonide 7
and finally reductive removal of the chiral auxiliary to give
stereochemically homogeneous alcohol 8 after chromatographic
purification (69% isolated yield from 6a). The C7,C9-anti relative
stereochemistry of 8 was confirmed by analyzing its 13C NMR
spectrum, in which the signals due to the quaternary carbon and
the two methyl carbons of the acetonide moiety were observed at
100.6, 24.9 and 23.5 ppm respectively, in good accordance with the
data for analogous 1,3-anti-diol acetonides.6 Finally, the alcohol
(8) was oxidized with Dess–Martin periodinane (DMP)7 to give
the C5–C11 fragment (9).
In the course of screening for plant growth regulators produced by
epiphytic microorganisms on live plants, Igarashi and co-workers
have recently isolated two novel polyketidic acids, pteridic acids A
(1) and B (11-epi-1), from the fermentation broth of Streptomyces
hygroscopicus TP-A0451 isolated from the stems of the bracken
Pteridium aquilinum, and determined their structures on the basis
of spectroscopic analyses including HMBC and NOESY experi-
ments (Fig. 1).1 They both exhibited a potent promoting activity in
the formation of adventitious roots in the hypocotyls of kidney
beans comparable to that of indol-3-acetic acid (auxin) at a very
low concentration of 1 nM. Our interest in the substantial
biological roles of secondary metabolites of microbial origin in the
natural ecosystem2 as well as the complex molecular architecture
of pteridic acids featuring a spiroacetal ring and eight stereogenic
centers around it prompted us to embark on the total synthesis of
pteridic acids. We describe herein the first enantioselective total
synthesis of pteridic acid A (1).
The preparation of the C12–C16 fragment (5) is shown briefly
in Scheme 2. The hydroxyl group of known ester 108 was protected
Pteridic acid A (1) was divided retrosynthetically into four
fragments, 2, 3, 4 and 5, by cleaving the C4–C5, C7–C8 and C11–
C12 bonds (Fig. 1). These C–C bonds were considered to be
installable by the Wittig olefination, Evans aldol reaction and
acetylenic coupling, respectively. To construct the C5–C11 portion
of pteridic acid A (i.e. 9, Scheme 1), our synthesis began with
the Evans asymmetric aldol reaction between 33 and 4,4 which
Scheme 1 Reagents and conditions: a) 3, Sn(OTf)2, Et3N, CH2Cl2,
278 uC, 78%; b) NaBH(OAc)3, AcOH, rt, 92%; c) Me2C(OMe)2,
TsOH?H2O, acetone, 30 uC, 96%; d) LiBH4, MeOH, THF, rt, 78%; e)
DMP, Py, CH2Cl2, rt, 94%.
Fig. 1 Retrosynthetic analysis of pteridic acid A.
Scheme 2 Reagents and conditions: a) ethyl vinyl ether, PPTS, CH2Cl2,
0 uC; b) DIBAL, CH2Cl2, 278 uC; c) DMSO, (COCl)2, Et3N, CH2Cl2,
278 uC, 69% from 10; d) CBr4, Ph3P, Py (4.2 eq.), CH2Cl2, 0 uC; e)
n-BuLi, THF, 278 uC, 51% from 11.
{ Electronic supplementary information (ESI) available: 1H NMR spectra
for compounds 5, 9, 14a, 14b, 14c, 15a, 15b, 15c and 1. See http://
www.rsc.org/suppdata/cc/b4/b416309e/
*skuwahar@biochem.tohoku.ac.jp
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(DDQ, CH2Cl2–pH 7 phosphate buffer), which caused partial
epimerization at the spiro-center, affording an inseparable 6:1
mixture of 14c and its C11-epimer. The Dess–Martin oxidation of
the epimeric mixture containing 14c as the major component
(14cA15a) was followed by four-carbon chain-elongation using
the C1–C4 fragment (2) (15aA15b) and subsequent removal of the
acetyl protecting group to yield a mixture of hydroxy esters, from
which 15c could be isolated by SiO2 chromatography (76% yield
from 14c).9 The 1H NMR spectrum of 15c was identical to that of
an authentic sample previously prepared by Igarashi et al. from
natural pteridic acid A.1 Finally, hydrolysis of the methyl ester
completed the enantioselective total synthesis of pteridic acid A (1)
{[a]24 + 24 (c 0.15, CHCl3); lit.1 [a]24 + 22.3 (c 1.0, CHCl3)}.10
D
D
1
The H and 13C NMR spectra of 1 were identical to those of
natural pteridic acid A. The enantiomeric homogeneity of our
1
synthetic pteridic acid A was assured by comparison of the H
NMR spectra of (S)-MTPA-ester samples (15d) prepared from
synthetic 15c and from authentic 15c which was previously derived
from natural pteridic acid by Igarashi et al.1
In conclusion, the first total synthesis of (+)-pteridic acid A (1)
was accomplished in 8.4% overall yield from the known
oxazolidinone derivative (4) through 16 steps including the
Evans asymmetric aldol reaction, acetylenic coupling and Wittig
olefination as the key C–C bond forming steps, which confirmed
the structure of 1 including its absolute configuration. Attempts to
obtain pteridic acid B9 and to apply the present synthetic strategy
to the synthesis of structurally related natural products such as
halichoblelide (a cytotoxic macrolide)11 and elaiophylin (an
antibiotic)8,12 are now underway.
We are grateful to Prof. Igarashi (Toyama Prefectural
University) for providing us with the copies of the NMR spectra
of pteridic acids A and B. This work was supported, in part, by
a Grant-in-Aid for Scientific Research (B) from the Ministry
of Education, Culture, Sports, Science and Technology of Japan
(No. 16380075).
Scheme 3 Reagents and conditions: a) 5, n-BuLi, THF, 278 uC, 40%; b)
DMP, Py, CH2Cl2, rt, 93%; c) CSA, CH2Cl2–MeOH (7.5:1), rt, 78%; d)
H2, Lindlar catalyst, 1-hexene–EtOAc (1:1), rt; e) PPTS, toluene, rt, 88%
from 13; f) Ac2O, DMAP, Py, rt, quant.; g) DDQ, CH2Cl2–pH 7
phosphate buffer (10:1), 0 uC, 87%; h) DMP, Py, CH2Cl2, rt; i) 2,
LiHMDS, THF, 278 uC, 91% from 14c; j) MeOH, K2CO3, rt, 83%; k)
KOH, MeOH–H2O (2:1), rt, 99%.
Takashi Nakahata and Shigefumi Kuwahara*
Laboratory of Applied Bioorganic Chemistry, Graduate School of
Agricultural Science, Tohoku University, Tsutsumidori-Amamiyamachi,
Aoba-ku, Sendai, 981-8555, Japan.
as the ethoxyethyl ether and the ester group was reduced to give an
alcoholic intermediate, which was then oxidized to aldehyde 11.
Dibromomethylenation of 11 in the presence of pyridine,
proceeded cleanly to give the corresponding dibromo-olefin
intermediate. The presence of pyridine was essential in this
reaction because its absence caused complete deprotection of the
ethoxyethyl protecting group. Finally, dehydrobromination of the
olefinic intermediate furnished the C12–C16 fragment (5).
E-mail: skuwahar@biochem.tohoku.ac.jp; Fax: 81 22 717 8783
Notes and references
1 Y. Igarashi, T. Iida, R. Yoshida and T. Furumai, J. Antibiot., 2002, 55,
764.
2 Y. Igarashi, R. Yoshida and T. Furumai, Regulation of Plant Growth &
Development, 2002, 37, 63; Y. Igarashi, T. Iida, T. Sasaki, N. Saito,
R. Yoshida and T. Furumai, Actinomycetologica, 2002, 16, 9.
3 M. G. Organ and J. Wang, J. Org. Chem., 2003, 68, 5568.
4 D. A. Evans, J. S. Clark, R. Metternich, V. J. Novack and
G. S. Sheppard, J. Am. Chem. Soc., 1990, 112, 866.
5 D. A. Evans, K. T. Chapman and E. M. Carreira, J. Am. Chem. Soc.,
1988, 110, 3560.
6 S. D. Rychnovsky, B. N. Rogers and T. I. Richardson, Acc. Chem. Res.,
1998, 31, 9; F. Eustache, P. I. Dalko and J. Cossy, J. Org. Chem., 2003,
68, 9994.
7 D. B. Dess and J. C. Martin, J. Org. Chem., 1983, 48, 4155.
8 D. A. Evans and D. M. Fitch, J. Org. Chem., 1997, 62, 454.
9 The silica gel column chromatography (hexane/ethyl acetate,
50:1A10:1) gave pure 15c (76% isolated yield) and a mixture of 15c
and 11-epi-15c originating from 11-epi-14c, which in turn was produced
by partial epimerization of the spiro-center during the conversion of 14b
into 14c. The mixture of esters could be saponified with KOH–H2O–
MeOH into a mixture of pteridic acids A (1) and B (2). Although the
The acetylide anion prepared from 5 was added to aldehyde 9 to
give 12a as a mixture of epimeric alcohols at C11 (Scheme 3). The
chemical yield of this step was moderate (40%) owing to the
concurrent b-elimination of 9 leading to the corresponding
a,b-unsaturated aldehyde. After oxidation of 12a to acetylenic
ketone 12b, the product was exposed to acidic conditions (CSA,
CH2Cl2–MeOH) to remove the two acetal protecting groups,
which brought about concomitant cyclic acetal formation to give
13 as a 3:1 epimeric mixture. Catalytic semi-hydrogenation of 13
and subsequent spiroacetal ring-formation using PPTS in toluene
gave 14a as a single stereoisomer. The stereochemistry of the spiro-
center of 14a was tentatively assigned based on the anomeric effect.
Conversion of 14a into the corresponding acetate (14b) was
followed by oxidative removal of the PMB protecting group
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presence of pteridic acid B in the saponification product mixture was
assured by the H NMR spectrum of the mixture, we were unable to
fully purify 2 because of its scarcity.
center of pteridic acids depicted in their paper1 was erroneous and the
correct stereochemistry should be represented by structure 1 shown in
this paper.
11 T. Yamada, K. Minoura and A. Numata, Tetrahedron Lett., 2002, 43,
1721.
12 K. Toshima, K. Tatsuta and M. Kinoshita, Bull. Chem. Soc. Jpn., 1988,
61, 2369.
1
10 Igarashi et al. originally reported the specific rotation value of pteridic
acid A to be 222.3.1 However, they recently informed us that the minus
sign was a typing error and the real sign was plus (+). They also
informed us that the absolute configuration of the C10-stereogenic
1030 | Chem. Commun., 2005, 1028–1030
This journal is ß The Royal Society of Chemistry 2005