employed to prepare 2,4-disubstituted oxetan- and azeti-
din-3-ones because it utilizes alkynes as starting materials.
We have devised a new strategy for the synthesis of four-
and five-membered heterocyclic compounds, which relies
on the utilization of phosphonate-ester6 cyclization reac-
tions (Scheme 1). Below, we describe the results of an
investigation to probe the viability of this strategy, which
has resulted in the development of a novel approach to the
synthesis of oxetan-, azetidin-, dihydrofuran- and pyrroli-
din-3-ones, and a synthesis of (()-pseudodeflectusin.
olefination reaction to generate 3a in 75% yield (2.6:1.0
E/Z mixture).
Table 1. Conditions for the Cyclization Reaction of 1a to form
Oxetan-3-one 2
Scheme 1. Synthetic Strategy for Substituted Oxetan-, Azetidin-
, Dihydrofuran- and Pyrrolidin-3-ones
entry
base
NaH
additive
temp (°C) t (h) yield (%)a
1
2
3
4
5
6
7
8
9
ꢀ78 to 0
2
3
3
3
3
3
3
3
3
N.R.b
trace
trace
23
NaHMDS
KHMDS
LiHMDS
LDA
ꢀ78 to 0
ꢀ78 to 0
ꢀ78 to 0
ꢀ78 to 0
41
LDA
0
0
0
0
63
LDA
12-crown-4
HMPA
70
In the first phase of this effort, we explored cyclization
reactions of the phosphonate-ester 1a.7 We observed that
treatment of 1a with NaH does not result in the formation
of the phosphono-oxetanone 2 (Table 1, entry 1) and that
utilization of either NaHMDS or KHMDS as bases leads
to formation of only trace amounts of the desired product
(Table 1, entries 2 and 3). In contrast, LiHMDS and LDA
are effective in promoting the cyclization reaction con-
ducted at ꢀ78 °C, which yields product 2 in 23% and 41%
respective yields (Table 1, entries 4 and 5). Increasing the
reaction temperature to 0 °C (Table 1, entry 6) and
including chelating agents, such as 12-crown-4, HMPA
and TMEDA that increase the nucleophilicity of the anion
intermediate, resultsinimproved yields(optimal 78%yield
using TMEDA, Table 1, entry 9) for the transformation of
1a to 2 (Table 1, entries 7ꢀ9).
LDA
72
LDA
TMEDA
78
a Diastereomer ratio of 2 was 2.2:1.0 in each case. b No reaction.
Scheme 2. Stepwise and One-pot Conversion of 1a to 3a
The results of further studies showed that 2 undergoes a
HWE reaction with benzaldehyde to afford an olefination
product. Specifically, treatment of 2 withLDAfollowed by
the addition of benzaldehyde leads to formation of 3a in
99% yield (2.6:1.0 E/Z mixture) (Scheme 2, eq 1). Impor-
tantly, the two processes converting 1a to 3a can be
conducted using a one-pot operation (Scheme 2, eq 2).
Accordingly, following treatment of 1a with LDA and
TMEDA in THF at 0 °C to form 2 (confirmed by using
TLC), PhCHO is added to the mixture promoting the
Having developed conditions for the one-pot 2-alkeny-
loxetan-3-one forming process, our attention next turned
to an exploration of the O,P-acetal 17 and aldehyde scope
ofprocess. A variety ofdialkyl-substituted O,P-acetals(1a,
1b and 1e), including those containing aromatic rings were
foundtoparticipate withPhCHO inthe two stepprocessto
give the corresponding 2-alkenyloxetan-3-ones 3a, 3b and
3e (Table 2, entries 1, 2 and 5). Interestingly, the presence
of a terminal alkene moiety in 1c does not affect the
cyclization and HWE reactions (Table 2, entry 3) and the
TBDPS (tert-butyldiphenylsilyl) group in 1d is not altered
under the reaction conditions that yield oxetan-3-one 3d
(70%) (Table 2, entry 4). The E/Z ratios of the products 3a,
3b and 3e formed in respective reactions of 1a, 1b and 1e
ranged from 2.1:1.0 to 5.8:1.0 (Table 2, entries 1ꢀ5).8
Moreover, aromatic aldehydes, containing electron donating
and withdrawing groups, participate in the two step
(6) We have explored novel reactivities of O,P-acetals generated from
O,O-acetal and phosphine and phosphite and developed some new
reactions. (a) Fujioka, H.; Goto, A.; Otake, K.; Kubo, O.; Yahata,
K.; Sawama, Y.; Maegawa, T. Chem. Commun. 2010, 46, 3976. (b)
Fujioka, H.; Goto, A.; Otake, K.; Kubo, O.; Sawama, Y.; Maegawa, T.
Chem. Commun. 2011, 47, 9894. (c) Maegawa, T.; Otake, K.; Goto, A.;
Fujioka, H. Org. Biomol. Chem. 2011, 9, 5648. (d) Fujioka, H.; Yahata,
K.; Kubo, O.; Sawama, Y.; Hamada, T.; Maegawa, T. Angew. Chem.,
Int. Ed. 2011, 50, 12232.(e) Goto, A.; Otake, K.; Kubo, O.; Sawama, Y.;
Maegawa, T.; Fujioka, H. Chem.;Eur. J. 2012, 18, 11423.
(7) O,P-acetal 1a was synthesized from the parent MOM ether by
treatment with TMSOTf and P(OMe)3. See Supporting Information for
detail.
(8) Absolute E/Z stereochemistry was not determined.
Org. Lett., Vol. 14, No. 18, 2012
4799