The reaction of ketone enolates with a δ-oxo phosphonate: A carbanion-based [4+2] annulation

Article abstract of DOI:10.1055/s-2001-14615

The reaction of ketone enolates with phosphonate aldehyde 3 followed by acetylation and cyclization represents a useful carbanion-based strategy for the appendage of a functionalized six-membered ring.

Full text of DOI:10.1055/s-2001-14615

LETTER
793
The Reaction of Ketone Enolates with a -Oxo Phosphonate:
A Carbanion-Based [4+2] Annulation
George A. Kraus,* Chauncey Jones
Department of Chemistry, Iowa State University, Ames, IA 50011, USA
Phone 515-294-7794; Fax 515-294-0105; E-mail: gakraus@iastate.edu
Received 21 February 2001
Michael addition reaction of triethyl phosphonoacetate
with 3-pentene-2-one.5 Unfortunately, this reaction did
not work with acrolein. Alkylation of triethyl phospho-
noacetate with 4-bromo-1-butene6 and NaH followed by
oxidation (NaIO4 (2.5 equiv), OsO4) produced 3 in 70%
yield.7
Abstract: The reaction of ketone enolates with phosphonate alde-
hyde 3 followed by acetylation and cyclization represents a useful
carbanion-based strategy for the appendage of a functionalized six-
membered ring.
Key words: annulation, cuprate addition, enolate
The soybean cyst nematode (SCN), Heterodera glycines,
has caused significant crop losses in the soybean industry.
A management strategy for the SCN that is cost effective
and compatible with sustainable agriculture has not yet
been developed.1 Masamune has shown that glycinoecl-
epin A (1) is a very effective hatching stimulus, capable of
initiating egg hatch at concentrations as low as 10-12 grams
per milliliter.2 As part of a biorational approach to nema-
tode management, we are using analogs of glycinoeclepin
A to effect premature hatching of SCN under conditions
where the nematode will not survive. Analog studies by
Murai3 and by Kraus4 have led to the identification of the
functionality necessary for activity. Significantly, Murai
has shown that the side chain containing the oxabicyclic
ketone is not required for activity. Analog 2 is a key syn-
thetic objective. As part of a direct approach to the synthe-
sis of 2, we developed the annulation described herein.
EtO2C
H
?
O
+
EtO2C
CHO
PO(OEt)2
OH
3
4
Although we were concerned that the ketone enolate
might abstract the acidic methine proton of the ester phos-
phonate rather than react with the aldehyde, the reaction
of cyclopentanone with LDA followed by aldehyde 3 led
to aldol 5 (R = H) in 80% yield. No products derived from
the intramolecular Wadsworth-Emmons cyclization were
detected. Attempts to force the cyclization by use of an
additional equivalent of base or by heating the alkoxide
led to the destruction of 5 (R = H). Protection of the alco-
hol as the THP ether produced some protected alcohol
plus significant amounts of dehydration product. Acetyla-
tion with acetic anhydride and 4-dimethylaminopyridine
and pyridine afforded the acetate in almost quantitative
yield. Treatment of 5 (R = Ac) with sodium hydride in
THF produced the acetoxy ester 6 in 81% yield as a mix-
ture of stereoisomers.8
O
A
B
O
HO2C
HO2C
C
OH
OH
D
EtO2C
HO2C
HO2C
PO(OEt)2
H
EtO2C
O
1. LDA, 3
NaH
O
1
2
2. A c2O
OAc
OR
6
5
A direct synthesis of the CD ring system might be accom-
plished if a suitable C ring precursor could be connected
onto a functionalized D ring. One possible reagent for this
transformation would be phosphonate 3. Our plan was
that the alkoxide produced by an aldol reaction of a ketone
enolate with 3 would intramolecularly abstract the me-
thine proton activated by the ester and the phosphonate,
leading to an intramolecular Wadsworth–Emmons reac-
tion and the production of 4. Although a literature search
indicated that aldehyde phosphonates such as 3 had not
been prepared, a related ketone had been prepared by the
By a similar procedure, ester 7 was prepared from the eno-
late of cyclohexanone in 80% yield as a mixture of diaste-
reomers. The reaction of the enolate of acetone with 3,
followed by acetylation and cyclization, afforded a 37%
yield of acetoxy ester 8 (R = Ac) and a 16% yield of hy-
droxy ester 8 (R = H).9 The reaction of the enolate of
3-pentanone with aldehyde 3 produced acetoxy ester 9
(R = Ac) in 79% yield as a mixture of stereoisomers. The
Synlett 2001 No. 6, 793–794 ISSN 0936-5214 © Thieme Stuttgart · New York

794
G. A. Kraus, C. Jones
LETTER
reaction of the enol silyl ether 10 with boron trifluoride The reaction of ketone enolates with phosphonate alde-
etherate and 3 in methylene chloride at 78 °C followed hyde 3 followed by acetylation and cyclization represents
by acetylation and cyclization afforded a 35% yield of es- a new carbanion-based strategy for the appendage of a
ter 11.
functionalized six-membered ring onto a ketone. This an-
nulation will permit the synthesis of analogs of 1 which
will be tested in nematode hatch assays.11 This sequence
proceeds under mild conditions and will be applicable to
other natural product systems.
EtO2C
EtO2C
R'
EtO2C
Me
Me
OTMS
OAc
OR
OAc
Me Me
R'
Me Me
Acknowledgement
8: R' = H
9: R' = Me
11
7
10
We thank the Iowa Soybean Promotion Board for financial support
of the research.
We next prepared ester 12 from 2-methyl-2-cyclopenten-
one. Lithium diallylcuprate was generated by the reaction
of allyltributylstannane with n-butyllithium followed by
addition of cuprous iodide. The resulting cuprate10 reacted
with 2-methyl-2-cyclopentenone and then aldehyde 3 to
provide the aldol in 78% yield. The aldol was acetylated
using acetic anhydride and DMAP to give acetoxy ketone
13 in 95% yield, as a mixture of isomers. The reaction of
13 with NaH in THF gave a 25% yield of ester 12. Several
bases were examined to improve the yield of this reaction.
Although lithium tert-butoxide or LiCl/DBN led to the
product in approximately 25% yield, potassium hexame-
thyldisilazane (KHMDS) in THF at 25 °C afforded a 42%
isolated yield of 12.
References and Notes
(1) Niblack, T. L.; Baker, N. K.; Norton, D. C. Plant Disease
1992, 76, 943.
(2) Masamune, T.; Anetai, M.; Takasugi, M.; Katsui, N. Nature
1982, 297, 495.
(3) Murai, A.; Ohkita, M.; Honma, T.; Hoshi, K.; Tanimoto, N.;
Araki, S.; Fukuzawa, A. Chem. Lett. 1992, 2103.
(4) Kraus, G. A.; Vander Louw, S.; Tylka, G. L.; Soh, D. J. Agric.
and Food Chem. 1996, 44, 1548.
(5) Deschamps, B.; Seyden-Penne, J. Tetrahedron 1977, 33, 413.
(6) Kraus, G. A.; Landgrebe, K. Synthesis 1984, 885.
(7) Spectra for 3. NMR (CDCl3) 9.74 (s, 1 H), 4.30-4.10 (m, 6 H),
3.06-2.93 (m, 1 H), 2.69-2.47 (m, 2 H), 2.29-2.16 (m, 2 H),
1.34-1.23 (m, 9 H). 13C NMR (CDCl3) 200.6, 168.8, 62.8,
61.6, 45.3, 43.6, 41.8, 19.6, 16.4, 14.3. IR (film) 2983, 2729,
1738, 1727, 1254 cm-1. Rf (ethyl acetate) = 0.18.
(8) Experimental: A 60% dispersion of NaH in mineral oil (2
equiv) was washed with pentane and suspended in dry THF (5
mL/mmole) under an argon atmosphere. A 0.1 M solution of
ketone (1 equiv) in THF was added dropwise at r.t. The
mixture was stirred at r.t. for 5 h, quenched with saturated
NH4Cl solution, extracted with ethyl acetate, dried over
Na2SO4, filtered and concentrated in vacuo. The residue was
purified by SGC.
CO2Et
O
PO(OEt)2
O
2 CuLi
Ac2O
3
OAc
13
EtO2C
(9) Data for 8 (R = Ac): NMR (CDCl3) 5.03-4.95 (m, 1 H), 4.19
(q, J = 7.2 Hz, 2 H), 2.52-2.16 (m, 4 H), 2.04 (s, 3 H), 1.99 (s,
3 H), 1.89-1.69 (m, 2 H), 1.29 (t, J = 7.2 Hz, 3 H). 13C NMR
(CDCl3) 170.7, 168.3, 142.4, 123.9, 68.8, 60.1, 38.5, 26.8,
23.7, 21.6, 21.4, 14.3. UV 209 nm.
(10) Lipshutz, B. H.; Crow, R.; Dimock, S. H.; Ellsworth, E. L.;
Smith, R. A. J.; Behling, J. R. J. Am. Chem. Soc. 1990, 112,
4063.
KHMDS
13
OAc
12
(11) Tylka, G. L.; Niblack, T. L.; Walk, T. C.; Harkins, K. R.;
Barnett, L.; Baker, N. K. J. Nematology 1993, 25, 596.
Article Identifier:
1437-2096,E;2001,0,06,0793,0794,ftx,en;S02201ST.pdf
Synlett 2001, No. 6, 793–794 ISSN 0936-5214 © Thieme Stuttgart · New York