Acid-mediated coupling of γ-hydroxybutenolides and aldehydes: Synthesis of a new class of spirocyclic ketal-lactones

Article abstract of DOI:10.1016/j.tetlet.2012.09.139

In the presence of trimethylsilyl trifluoromethanesulfonate (TMSOTf), γ-methyl-γ-hydroxybutenolide reacts with aromatic aldehydes to generate a new class of stereochemically rich spirocyclic ketal-lactones in good yields and with excellent stereoselectivities. We believe that this process takes place through the in situ generation of protoanemonin followed by a Prins reaction. Herein, we describe this discovery, along with substrate scope and preliminary mechanistic studies.

Full text of DOI:10.1016/j.tetlet.2012.09.139

Tetrahedron Letters 53 (2012) 6779–6781
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Acid-mediated coupling of
c-hydroxybutenolides and aldehydes: synthesis of
a new class of spirocyclic ketal-lactones
a
a,b,
⇑
Alberto Munoz , Ryan P. Murelli
a
Department of Chemistry, Brooklyn College, The City University of New York, 2900 Bedford Avenue, Brooklyn, NY 11210, United States
Department of Chemistry, The Graduate Center, The City University of New York, 365 Fifth Avenue, NY 10016, United States
b
a r t i c l e i n f o
a b s t r a c t
Article history:
In the presence of trimethylsilyl trifluoromethanesulfonate (TMSOTf), c-methyl-c-hydroxybutenolide
Received 4 September 2012
Revised 27 September 2012
Accepted 30 September 2012
Available online 12 October 2012
reacts with aromatic aldehydes to generate a new class of stereochemically rich spirocyclic ketal-lactones
in good yields and with excellent stereoselectivities. We believe that this process takes place through the
in situ generation of protoanemonin followed by a Prins reaction. Herein, we describe this discovery,
along with substrate scope and preliminary mechanistic studies.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Spirocycles
Prins reaction
c
-Hydroxybutenolides
c
-Hydroxybutenolides are heterocyclic structures found in a
our product by silica gel chromatography. Other Lewis acids such
as chlorotrimethylsilane or zirconium tetrachloride did not lead
to product, nor did the Bronsted acid, toluenesulfonic acid (Table 1,
1
variety of natural products that can be synthesized readily
through the oxidation of furan.2 While underexplored as syn-
thons, they have also found some utility as synthetic precursors
to complex lactone-containing compounds. For example, upon
–4
entries 5–7). In these instances the acids isomerized the
c-
hydroxybutenolide to the open, trans form (4).
acylation of
the resulting compounds can be used in dynamic kinetic asymmet-
ric palladium-catalyzed coupling reactions.5 In addition,
c
-hydroxybutenolides, it has been demonstrated that
A substrate scope study revealed that the nitro group can be put
at either the ortho or para positions while still providing moderate
yields (3b and 3c). Other electronically poor aryl aldehydes, such as
meta-chloro and meta-trifluoromethylbenzaldehyde work as well
(3d and 3e). When benzaldehyde was used, we saw a significant
decrease in yield (3f). Increasing the amount of aldehyde to
20 equiv, however, led to an increase in yield from 18% to 48%.
c
-
hydroxybutenolides can react in cascade reactions with molecules
6
such as isocyanates (Scheme 1, Eq. 1) and ketenes (Scheme 1, Eq.
7
2
)
to generate complex bicyclic lactones, and have been impli-
8,9
cated as synthons in natural product biosynthesis. Given their
convenient preparation and bond-forming potential, our group
O
has been interested in further exploration of the reactivity of
hydroxybutenolide-containing molecules. In the course of our
studies it was revealed that aromatic aldehydes react with
methyl- -hydroxybutenolides under strongly acidic conditions to
generate novel spirocyclic ketal-lactones (Scheme 1, Eq. 3).
c-
O
O
O
RNCO
c
-
eq. 1
O
c
HO
ref. 6
NR
O
Optimization of this reaction was performed with 3-nitrobenz-
aldehyde as the carbonyl source (Table 1). The reaction works best
with triflate acids, as both trimethylsilyltriflate and triflic acid pro-
vided comparably high yields (Table 1, entries 1 and 2). The opti-
mal amount of acid is 2 equiv, as lowering the equivalency to 1
brings the reaction yield down significantly (Table 1, entry 3). In
addition, the optimal amount of aldehyde was found to be 6 equiv
Ph P
O ;
3
O
O
O
O
(HCHO)n
eq. 2
eq. 3
O
O
O
HO
ref. 7
Ar
O
ArCHO, Acid
O
O
O
HO
H C
(Table 1, entry 4). The excess aldehyde was easily separable from
O
3
This work
Ar
⇑
Corresponding author. Tel.: +1 718 951 5000x2821; fax: +1 718 951 4607.
E-mail address: rpmurelli@brooklyn.cuny.edu (R.P. Murelli).
Scheme 1. Examples of
c
-hydroxybutenolide cascade reactions.
0
040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.09.139

6
780
A. Munoz, R. P. Murelli / Tetrahedron Letters 53 (2012) 6779–6781
Table 1
Select examples from optimization studies
Entry
Acid
Equiv of acid
Equiv 2
% Yield 3aa
Scheme 3. Proposed mechanism for formation of 3a–i.
1
2
3
4
5
6
7
TMSOTf
TfOH
TMSOTf
TMSOTf
2
2
1
2
2
2
2
6
6
6
3
6
6
6
90
90
53
47
0
stereocenters (3h). In this instance, reaction yields were lower,
and the additional stereocenter was introduced without any selec-
tivity. Finally, while aliphatic aldehydes did not work, paraformal-
dehyde could be used as the source of carbonyl. The product in this
instance, 3i, was significantly less stable than other substrates
made, and the lower yield obtained is believed to be at least in part
due to the instability to chromatographic conditions.
ZrCl
4
TMSCl
TsOH
0
0
a
Isolated yields following silica gel chromatography.
In our proposed mechanism, elimination of water and/or
TMSOH takes place under the acidic conditions to generate the
known molecule protoanemonin (5, Scheme 3). Protoanemonin
Aldehydes toward the more electronically rich extremes, such as 4-
anisaldehyde and 2-furaldehyde, did not lead to any noticeable
amounts of product (results not shown). However, attenuating
the electronics of the furan by introducing a nitro group did allow
for furans to be incorporated (3g). Taken together, these reactions
indicate that electronically poor aldehydes work best under the
reaction conditions.
1
0
then undergoes a Prins reaction with 2 equiv of the aldehyde to
1
1
form 3a–i. When studies were carried out in deuterated chloro-
1
form, and the reaction was monitored by H NMR, no protoanemo-
nin was observed. However, when
1) was treated with triflic acid in the absence of the aldehyde, pro-
tons consistent with those reported for protoanemonin were ob-
c-methyl-c-hydroxybutenolide
(
c
-Ethyl-
c
-hydroxybutenolide can also be used in place of
c-methyl-c-hydroxybutenolide, and generate a molecule with 4
1
2
served. Adding the aldehyde subsequently led to product, albeit
1
3
with noticeably diminished efficiency. We see this as evidence
that the productive coupling reaction is competing with non-pro-
ductive side reactions of protoanemonin. Thus, we believe that
the higher equivalents of aldehyde lead to a higher yielding process
by increasing the rate of the productive reaction.
We believe 3a–i are thermodynamic products, and form via the
reversible nature of our proposed transformation. As can be seen in
Scheme 2, the two aryl groups on the six-membered dioxane ring
sit in the equatorial position, and the butenolide is connected with
its carbon–oxygen bond axial as would be predicted as thermody-
namically favorable using an anomeric effect argument. This ste-
reochemistry was solved using NOESY correlative experiments,
and confirmed with crystal structure analysis. The non-selective
nature of the methyl stereocenter of 3h suggests that conversion
of 5 to 6 proposed in Scheme 3 is not reversible.
We then re-subjected product 3a to the reaction conditions in
the presence of benzaldehyde to gauge the reaction’s reversibility.
Scheme 2. Substrate scope studies. (a) Reactions were run with 20 equiv of
aldehyde; (b) -ethyl- -hydroxybutenolide was used as butenolide, and products
were isolated as mixture of diastereomers; (c) 5.25 mass equivalents of
paraformaldehyde were used as carbonyl source.
c
c
a
Scheme 4. Aldehyde exchange experiments.

A. Munoz, R. P. Murelli / Tetrahedron Letters 53 (2012) 6779–6781
6781
This experiment yielded partial incorporation of the aldehyde, but
only into the position shown (Scheme 4, 3a ? 8), consistent with
our hypothesis. In this instance, approximately 30% conversion
was observed, as the starting material was isolated along with 8
in a 2:1 ratio. The partial conversion is believed to be due to the
lower stability of electronically poor carbonyls, thus shifting the
ate research fellowship to A.M. provided by The National Science
Foundation’s NYC Louis Stokes Alliance for Minority Participation
Program (NYC-LSAMP, HRD #0703449). Finally, the authors thank
William W. Brennessel (X-ray Crystallographic Facility, Depart-
ment of Chemistry, University of Rochester) for his X-ray crystallo-
graphic studies, and Americo Fraboni and Beth Manes for early
experimental support.
1
4
global equilibrium to limit nitrobenzaldehyde formation. To test
this hypothesis, we then subjected phenyl-containing compound
3
3
f to the reaction conditions with 3-nitrobenzaldehyde (Scheme 4,
f ? 9). In this instance, full incorporation of 3-nitrobenzaldehyde
Supplementary data
was observed, leading exclusively to 9. Regardless of the features
influencing the relative incorporation, these studies demonstrate
that the reaction is reversible at the steps that lend the relative ste-
reochemistry, and help support the hypothesis that the high dia-
stereoselectivity is thermodynamically driven.
Crystal structure cif file of 3a can be requested from Cambridge
Crystallographic Database (http://www.ccdc.cam.ac.uk/) using
deposition number CCDC 899874.
Supplementary data (experimental procedures and spectral
data) associated with this article can be found, in the online ver-
sion, at http://dx.doi.org/10.1016/j.tetlet.2012.09.139. These data
include MOL files and InChiKeys of the most important compounds
described in this article.
There are several aspects of this reaction that we find notewor-
thy. For one, protoanemonin (5) is a toxic metabolite found in a
1
2
variety of plants, and has demonstrated efficiency as a synthon
1
5
16
in both Diels–Alder and dipolar cycloaddition reactions. In both
instances, the reaction takes place exclusively with the exocyclic
unsaturated alkene over the internal -unsaturated alkene, which
c-
References and notes
c
is consistent with the proposed Prins reaction described here-in.
While synthesizing protoanemonin can be done in a two step se-
quence from c-angelica lactone, handling and storing protoanem-
onin can be troublesome, requiring stabilizers such as
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1
2
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c
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1
7
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The authors are grateful for generous financial support from
Brooklyn College, and funding from the National Institutes of
Health (1SC2GM099596). We are also grateful for an undergradu-