Lewis base-catalyzed divergent isomerizations of 5-hydroxyl-2,3-dienoate

Article abstract of DOI:10.1016/j.tetlet.2013.10.059

A divergent isomerization of 5-hydroxyl-2,3-dienoate 1 catalyzed by Lewis base has been developed, the phosphine catalyst leads to 5-oxohex-2(3)-enoates 2 while DABCO catalyst affords 3-ethoxy α,β-unsaturated lactone 3.

Full text of DOI:10.1016/j.tetlet.2013.10.059

Accepted Manuscript
Lewis Base-Catalyzed Divergent Isomerizations of 5-Hydroxyl-2,3-dienoate
Wei Dong, Pengfei Hu, Jian Hu, Xiaofeng Tong
PII:
S0040-4039(13)01794-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.10.059
TETL 43697
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
22 August 2013
29 September 2013
14 October 2013
Please cite this article as: Dong, W., Hu, P., Hu, J., Tong, X., Lewis Base-Catalyzed Divergent Isomerizations of
5-Hydroxyl-2,3-dienoate, Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.10.059
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Graphical Abstract

Lewis Base-Catalyzed Divergent Isomerizations of
5-Hydroxyl-2,3-dienoate
Wei Dong, Pengfei Hu, Jian Hu and Xiaofeng Tong*1
Shanghai Key Laboratory of Functional Materials Chemistry, East China University of Science
and Technology, Shanghai 200237, P. R. China.
Abstract: A divergent isomerization of 5-hydroxyl-2,3-dienoate 1 catalyzed by Lewis base has
been developed, the phosphine catalyst leads to 5-oxohex-2(3)-enoates 2 while DABCO catalyst
affords 3-ethoxy α,β-unsaturated lactone 3.
Keywords: Lewis Base; isomerization; 5-hydroxyl-2,3-dienoate
Lewis base catalysis has emerged as a rapidly growing area of research interest and
has been a robust synthetic tool to produce numerous densely functionalized
compounds.1 The catalytic use of Lewis base has been most intensively investigated
and demonstrated in such as Morita-Baylis-Hillman reaction2, Rauhut-Currier
reaction3, Lu’s type cycloaddtion4, [2+2] cycloaddition5, umpolung addition6 and so
on. With sharp contrast to the highly active situation of the above-mentioned reactions,
rare efforts have been devoted to the phosphine-catalyzed isomerization of activated
allene and alkyne to (E,E)-1,3-diene. No variant of this isomerization, to the best of
our knowledge, has been developed since it was independently discovered by Trost
and Lu in 1990s,7 although its synthetic applications have been elegantly
demonstrated.8 Herein, we report a novel phosphine-catalyzed isomerization of
5-hydroxyl-2,3-dienoate 1 to 5-oxohex-2(3)-enoates 2 (Scheme 1a). Furthermore, it is
interesting to find that the isomerization of 1 is switched to afford lactone 3 when
DABCO is instead used as the catalyst (Scheme 1b).
Scheme 1. Lewis Base-Catalyzed Divergent Isomerizations of 2,3-dienoate 1
1
Corresponding author. Tel.: +086-21-64253881; fax: +086-21-64253881; e-mail: tongxf@ecust.edu.cn

Scheme 2. Working Hypothesis for Phosphine-Catalyzed Isomerization of 1 to 2
Our design plan was prompted by the generally accepted mechanism for the
PPh3-catalyzed isomerization of allenoate. The working hypothesis for the
isomerization of 1 to 2 is depicted in Scheme 2. Addition of triphenylphosphine to
allenoate 1 results in the formation of zwitterionic resonants A1 and A2. Then, the
former intermediate A1 undergoes continuous proton shifts to generate intermediate C.
In the case of phosphine-catalyzed isomerization of allenoate, an acid co-catalyst is
typically required to facilitate the corresponding proton shifts.9 The hydroxyl group of
allenoate 1 might play a similar role as the acid co-catalyst. Thus, no requirement of
external acid co-catalyst could be anticipated for the isomerization of 1 to 2.
Subsequently, intermediate D, which is a resonance form of C, undergoes proton shift
to form intermeidate E, which is followed by 1,4-elimination of phosphine catalyst to
give product 2. As part of our ongoing effort in Lewis base catalysis,10 we set out to
investigate this possibility.
Thus, we initially chose compound 1a as the model substrate in order to establish
an optimal reaction conditions (Table 1). With 20 mol% triphenylphosphine as the
catalyst and toluene as the solvent, we were delighted to find that the isomerization of
1a smoothly occurred at room temperature, affording product 2a in 54% yield (Table
o
1, entry 1). When the reaction was carried out at 50 C, the yield of 2a was improved
to 80%, and further elevating the temperature proved unnecessary (Table 1, entries 2

and 3). Based on these results, some other phosphines, such as
tris(4-fluorophenyl)phosphine, tris(furan-2-yl)phosphine as well as tributylphosphine,
were also explored. However, they did not exhibit any superior performance than
PPh3 (Table 1, entries 4-6). After brief screening of solvent, we identified that toluene
was an optimal choice (Table 1, entries 7-9).
Table 1. Optimization of Reaction Conditions for Isomerization of 1a to 2a.a
entry cat.
solvent
toluene
toluene
toluene
T (oC)
25
Yield (%)b
1
2
3
4
5
6
7
8
9
PPh3
54
80
67
72
64
58
63
45
73
PPh3
PPh3
50
80
P(4-F-C6H4)3 toluene
50
P(2-furan)3
(nBu)3P
PPh3
toluene
toluene
THF
50
50
50
PPh3
MeOH
DCM
50
PPh3
50
a Reaction conditions: 1a (0.2 mmol), phosphine (0.04 mmol), 4 mL solvent. b Isolated yield.
Table 2. Phosphine-catalyzed Isomerization of 1 to 2a
entry 1 (R)
2
Yield (%)b
1
2
3
4
5
6
7
8
9
1a (Ph)
80
54
2a
2b
2c
2d
2e
2f
1b (4-Me-C6H4)
1c (4-MeO-C6H4)
1d (4-Br-C6H4)
1e (nPr)
73
54
92
1f [-(CH2)2Ph]
1g [-(CH2)2OTBS]
1h (styryl)
85
85
2g
2h
2i
NRc
1i (H)
NRc
a Reaction conditions: 1a (0.2 mmol), phosphine (0.04 mmol), 4 mL toluene. Isolated yield. c NR
b
= no reaction.

With the optimized reaction condtions in hand, we then investigated the scope and
limitation of the PPh3-catalyzed isomerization of 1 to 2. The results are summarized in
Table 2. In general, the triphenylphosphine-catalyzed isomerization can be achieved
with aryl- and alkyl-substituted substrates. The aromatic ring can bear an
electron-donating or an electron-withdrawing group. However, the electronic
influence of aromatic substituent shows no monotonous relationship with the
corresponding product yield (Table 2, entries 1-4). Alkyl-substituted substrates exhibit
much better performance, affording products 1e-1g in excellent yields (Table 2,
entries 5-7). It should be noted that substrate 1h bearing a styryl group and 1i were
found to be inert under the optimized conditions and both were recovered in 95%
yield, demonstrating the limitation of this isomerization (Table 2, entries 8 and 9).
Scheme 3. Gram-scale Synthesis of Substituted Benzoate 4
5-Oxohex-2(3)-enoates 2 are valuable building blocks and are obtained otherwise
with multiple synthetic steps.11 To illustrate this synthetic utility of the PPh3-catalyzed
isomerization, a preparative scale experiment was conducted. Indeed, 1.2 gram of 1e
was subjected to the standard reaction conditions and furnished 2e being isolated with
somewhat lower yield (Scheme 3). The obtained 2e reacted well with chaltone using
the protocol developed by Liu’s group,12 delivering 1.27 gram of benzene derivative
4.
Scheme 4. The Proposal for the DABCO-catalyzed Isomerization of 1e

Interestingly, when phosphine catalyst for the reaction of 1e was replaced by
catalytic amount of DABCO, lactone product 3e was isolated instead, albeit only in
32% yield (Scheme 4). These results demonstrate different catalytic behaviors
between phosphine and tertiary amine catalysts for the allenoate substrates.13 The
formation of lactone 3e can be explained by the proposed mechanism as outlined in
Scheme 4. 1,4-Addtion of DABCO catalyst to substrate 1e forms two resonants F1
and F2. Then, the latter undergoes proton shift to generate intermediate G, which
facilitates intramolecular lactonization to produce intermediate H and release a
molecule of ethanolate which initiates an addition-elimination process to yield
product 3e and regenerate DABCO catalyst (Scheme 4).14
Although we have no supporting data to elucidate these two divergent
isomerizations at this stage, we believed that resonant A1 might be
thermodynamically favorable over A2 in the phosphine case, while resonant F2 might
be favorable in the DABCO case. Furthermore, δH of intermediate B locates at allylic
position of electron-deficient alken. Thus it might be readily deprotonated. Apparently,
δH of intermediate G is lack of the corresponding activation effect.
Table 3. DABCO-catalyzed isomerization of 1 to 3a
entry 1 (R1, R2)
Yield (%)b
3
1
2
3
4
5
6
7
8
1e (R1 = nPr, R2 = H)
92
90
3e
3f
1f [R1 = -(CH2)2Ph, R2 = H]
1g [R1 = -(CH2)2OTBS, R2 = H]
1i (R1 = H, R2 = H)
93
3g
3i
87
1j (R1 = Bn, R2 = H)
80
3j
1k (R1 = Me, R2 = Me)
1a ((R1 = Ph, R2 = H)
71
3k
3a
3h
NRc
NRc
1h (R1 = styryl, R2 = H)
b
a Reaction conditions: 1a (0.2 mmol), DABCO (0.04 mmol), 4 mL solvent. Isolated
yield. c NR = no reaction.
To our delight, the isolated yield of 4e could be improved to 92% when ethanol was
instead used as solvent (Table 3, entry 1). Under these conditions, a wide range of
substrates with an alkyl substituent at δC-position smoothly undergo isomerization to

afford the corresponding latones 4 in good to excellent yields (Table 3, entries 1-6).
To our surprise, no reaction was observed when substarte 1a or 1h was subjected to
these reaction conditions (Table 3, entries 7 and 8).
When the DABCO-catalyzed isomerization of 1 was conducted in MeOH solvent,
the corresponding 3-methoxy α,β-unsaturated lactone could be obtained. Indeed, with
the use of MeOH as the solvent, substrate 1f was smoothly transformed into
(+/-)-dihydrokavain 5f15 in 90% yield (eq 1). Furthermore, under the otherwise
identical reaction conditions, MeOH-d4 enabled deuterium-labeled 5e being isolated
in 90% yield, which has 97% D at C3-position and 79% D at C5-position (eq 2).
Although numerous methods have been elegantly developed to access the related
lactones of widely synthetic and biological interest,16 the present DABCO-catalyzed
isomerization of 1 provides an alternative way, which features mild conditions, simple
operation as well as facile deuterium-labeling.
To further demonstrate the utility of the DABCO-catalyzed isomerization, we
sought to undertake a stereospecific synthesis of latone (R)-5l, which is an important
intermediate for the total synthesis of natural product vioxanthin.17 Thus, using a
modified Fu’s Cu-catalyzed protocol,18 coupling between commercial ethyl
2-diazoacetate
and
(R)-3-butyn-2-ol
(99%
ee)
afforded
(R)-ethyl
5-hydroxyhexa-2,3-dienoate 1l, which was smoothly converted into (R)-5l in 85%
yield over the two steps, (Scheme 5). Importantly, the spectroscopic data for the
obtained (R)-5l in this way is in complete agreement with that in the literatures.

Scheme 5. Synthesis of Lactone (R)-5l in Two Steps
In summary, we have developed the Lewis base-catalyzed divergent isomerizations
of 5-hydroxyl-2,3-dienoate 1. The isomerization of 1 to 5-oxohex-2(3)-enoates 2 was
achieved by using the phosphine catalyst, which presents a novel variant of
phosphine-catalyzed isomerization of activated allene. On the other hand, the
DABCO catalyst furnished the isomerization of 1 to 3-ethoxy α,β-unsaturated lactone
3. Both of the resulted products are important compounds of widely synthetic and
biological interest. Further understanding of mechanism via computational studies and
synthetic application are ongoing and will be reported in due course.
Acknowledgment: We are grateful for the financial support from NSFC (No.
21002025 and 21272066), NCET (No. 12-0851), Fundamental Research Funds for the
Central Universities, Shanghai Rising-Star Program (11QA1401700), and Fok
Ying-Tong Education Foundation for Young Teachers in the Higher Education
Institutions of China (131011).
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