Enantioselective synthesis of a simple benzenoid analogue of glycinoeclepin a

Article abstract of DOI:10.1021/ol8024633

(Chemical Equation Presented) A synthesis of the readily accessible glycinoeclepin A analogue 2 is reported.

Full text of DOI:10.1021/ol8024633

ORGANIC
LETTERS
2008
Vol. 10, No. 24
5617-5619
Enantioselective Synthesis of a Simple
Benzenoid Analogue of Glycinoeclepin A
Simon Giroux and E. J. Corey*
Department of Chemistry and Chemical Biology, HarVard UniVersity, 12 Oxford
Street, Cambridge, Massachusetts 02138
corey@chemistry.harVard.edu
Received October 24, 2008
ABSTRACT
A synthesis of the readily accessible glycinoeclepin A analogue 2 is reported.
Glycinoeclepin A (1), a biosynthetic product of the
soybean plant, diffuses from the plant roots into the soil
where, at concentration as low as 10-12 g/mL, it stimulates
hatching of eggs of the predatory nematode Heterodera
glycines.1 In the absence of a nearby growing plant, the eggs
of the nematode can remain unhatched and viable for many
months, emerging only when a plant becomes available. The
agricultural strategy of crop rotation is based on the disrup-
tion of this natural battle by spacing soybean crops over a
period of time larger than the survival time of the eggs of
H. glycines.
research to develop a biologically active mimic of glycino-
eclepin A that would be relatively simple to synthesize and
also sufficiently potent to be useful. Such a synthetic mimic
could be effective and practical even at levels of intrinsic
activity orders of magnitude below that of 1. Our initial
studies have focused on the tricyclic benzenoid analogue 2
of glycinoeclepin A. The selection of this analogue was
guided by the aim of trading off potency for synthetic
accessibility. Reported herein is a simple and potentially
practical synthesis of 2.
In principle, if the eggs of H. glycines could be induced
to hatch well in advance of the planting of new soybean
plants, destruction of the crop should be prevented, since
the lifetime of the hatched nematode itself is only a matter
of weeks. Thus, glycinoeclepin A (1) might be a useful
agrochemical. Unfortunately, 1 is produced only in trace
amounts by the soybean plant, and so naturally biosynthe-
sized glycinoeclepin A is essentially unavailable, even in
subgram amounts. Although glycinoeclepin A has been
obtained by total synthesis,2 the known synthetic processes
are too complex and costly to provide an unlimited and
inexpensive supply. We have, therefore, embarked on
Figure 1. Structure of glycinoeclepin A.
The synthesis of analogue 2 commenced with the con-
densation of 2-methylcyclopentanone and (R)-R-methylben-
zylamine and subsequent Michael reaction with tert-butyl
acrylate to provide the (S)-keto ester 3 (73% yield) after
acidic hydrolysis of the resulting imine.3 Conversion of 3 to
the corresponding vinyl triflate (NaHMDS, PhN(Tf)2, THF,
(1) (a) Fukuzawa, A.; Furusaki, A.; Ikura, M.; Masamune, T. J. Chem.
Soc., Chem. Commun. 1985, 221–222. (b) Masamune, T.; Anetai, M.;
Takasugi, M.; Katsui, N. Nature 1982, 297, 495–496.
10.1021/ol8024633 CCC: $40.75
Published on Web 11/13/2008
2008 American Chemical Society

Scheme 1. Synthesis of the Glycinoeclepin A Analogue 2
-78 °C) and subsequent palladium-catalyzed vinylation
[(Pd(PPh3)4 7.5 mol %, tributyl(vinyl)tin, LiCl, THF, 65 °C)]
afforded the diene 4 in 80% yield for the two-step sequence.
Heating 4 with dimethyl acetylenedicarboxylate (DMAD)
in toluene (sealed tube, 120 °C) led to a 1:1 mixture of
diastereomeric Diels-Alder adducts 5 which was oxidized
with MnO2 in refluxing benzene to provide benzenoid triester
6 (77%, two steps). Selective hydrolysis of the least hindered
methoxycarbonyl group was achieved using LiOH (1.5
equiv) in THF-MeOH-H2O (2:2:1) to provide the monoac-
id 7 in 83% yield. The reduction of acid 7 to aldehyde 8
was effected by a two-step procedure involving the formation
of the corresponding acid chloride [(COCl)2, DMF cat.,
CH2Cl2] followed by reduction using freshly prepared
LiAlH(O-t-Bu)3 in THF. The intermolecular aldol coupling
between ketone 94 and aldehyde 8, with concomitant
cyclization to the adjacent ester, proceeded smoothly using
LDA as base (THF, -78 to -30 °C) to give a mixture of
diastereomeric lactones 10 in 84% yield. The diastereomeric
mixture of lactones 10 proved to be resistant to reduction
using hydrogenation over Pd-C, PtO2, or Pd(OH)2 as
catalysts or using ionic reduction (TFA, Et3SiH). Eventually,
this difficulty was overcome by using NaOH (10 equiv) in
aqueous EtOH to generate the bright yellow enone 11 in
situ and exposure to Pd-C and H2 (1 atm) for 20 h, which
Scheme 2. Synthesis of Benzenoid Derivative 14
(2) (a) Murai, A.; Tanimoto, N.; Sakamoto, N.; Masamune, T. J. Am.
Chem. Soc. 1988, 110, 1985–1986. (b) Mori, K.; Watanabe, H. Pure Appl.
Chem. 1989, 61, 543–546. (c) Corey, E. J.; Houpis, I. N. J. Am. Chem.
Soc. 1990, 112, 8997–8998.
(3) Corey, E. J.; Wood, H. B. J. Am. Chem. Soc. 1996, 118, 11982–
11983, and references therein.
(4) Baigrie, L. M.; Seiklay, H. R.; Tidwell, T. T. J. Am. Chem. Soc.
1985, 107, 5391–5396.
5618
Org. Lett., Vol. 10, No. 24, 2008

resulted in the required product 12. Saponification of the tert-
butyl ester with NaOH in refluxing EtOH provided analogue
2 in 43% yield (over the last three steps).
We have also shown the feasibility of using the synthetic
strategy exemplified in Scheme 1 to access the tricyclic
phenolic diacid 15, which is an even closer analogue to
glycinoeclepin A than 2. The key steps are outlined in
Scheme 2.
Preliminary evaluation of glycinoeclepin analogue 2 has
revealed that it is capable of stimulating the hatching of H.
glycines at subnanomolar concentrations. More detailed
studies are underway to confirm this activity and to determine
the minimum concentration for effective hatching under a
range of conditions. Very extensive studies are required
because the larvae of H. glycines are encased in the bodies
of dead female nematodes and not free in soil. It is gratifying
that our initial research appears promising because H.
glycines has been estimated to reduce yields of soybean crops
by about 10%.5
Acknowledgment. S.G. is grateful to NSERC (Canada)
for a postdoctoral fellowship.
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL8024633
(5) We are indebted to Dr. Gregory Tylka of Iowa State University for
conducting the biological evaluation.
Org. Lett., Vol. 10, No. 24, 2008
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