Rapid synthesis of fused oxabicycles through the molecular rearrangement of spirocyclic ethers

Article abstract of DOI:10.1002/ejoc.201300832

A molecular rearrangement of 5,5-spirocyclic cyclopentenones to 5,6-fused cyclopentenones catalyzed by Amberlyst15 is described. This work emphasizes the utility of renewable resources, such as furfural, that can be transformed into a variety o

Full text of DOI:10.1002/ejoc.201300832

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201300832
Rapid Synthesis of Fused Oxabicycles through the Molecular Rearrangement
of Spirocyclic Ethers
Leoni I. Palmer,[a] Gesine K. Veits,[a] and Javier Read de Alaniz*[a]
Keywords: Rearrangement / Sustainable chemistry / Oxygen heterocycles / Spiro compounds / Ethers
A
molecular rearrangement of 5,5-spirocyclic cyclo-
formed into a variety of valuable products. It also highlights
the viability of 5,5-spirocycles as intermediates en route to
5,6-fused cyclopentenones.
pentenones to 5,6-fused cyclopentenones catalyzed by
Amberlyst®15 is described. This work emphasizes the utility
of renewable resources, such as furfural, that can be trans-
from one sustainable starting material through a molecular
rearrangement, see Figure 1 (c).
Introduction
The majority of industrial chemical processes are based
on petrochemical feedstock; limited supplies of crude oil
are declining, which has resulted in an ever-gaping need for
the development of routes to chemicals, materials, and fuels
from renewable resources such as biomass.[1] Materials de-
rived from nonedible renewable resources, ideally byprod-
ucts in food production processes, are consequently increas-
ingly valuable starting materials for chemistry. One such
raw material, furfural, is produced from hemicellulose de-
rived from agricultural waste products such as bagasse, oat
hulls, and corncobs.[2] In today’s increasingly globally con-
scientious society, environmentally benign stock chemicals
are important to sustainable development through ensuring
a future supply of raw materials.
In the USA, furfural is produced on an estimated scale
of 300000 tons annually at a current cost of $366/t.[3] With
this considered, it is no surprise that the chemistry of
furfural continues to inspire the development of new meth-
odologies[4] that are an asset to a number of research
areas.[5] Our recent work on the development of the aza-
Piancatelli reaction commenced with the synthesis of furyl-
carbinols from furfural and their subsequent conversion
into 4-aminocyclopentenones, see Figure 1 (a).[6] A natural
extension of this work was to investigate the intramolecular
reaction to make azaspirocycles [Figure 1 (b) X = ArN] as
well as the corresponding intramolecular oxa-Piancatelli re-
action to afford oxaspirocycles [Figure 1 (b) X = O].[6b,6c]
Over the course of these studies, it became apparent to us
that we were in the position to access two valuable products
Figure 1. Progress of the Piancatelli reaction.
To date, the isomerization of spirocyclic cyclopentenones
to fused cyclopentenones as shown in Figure 1 (c) is un-
known. To address this limitation and to provide efficient
access to fused oxabicycles, we decided to explore this mo-
lecular rearrangement. We were intrigued by this transfor-
mation because oxabicycles are an important class of com-
pounds in organic synthesis and they have served as key
intermediates in the total synthesis of numerous biologically
active molecules. Moreover, reaction design that conscien-
tiously incorporates renewable resources and facile pro-
cessing to access a different synthetically viable scaffold is
critical to the move toward global sustainability on a labo-
ratory scale. Herein, we report the optimization and scope
for the formation of oxabicycles 2 from oxaspirocycles 1,
both derived from one common starting material.
[a] Department of Chemistry & Biochemistry, University of
California,
Santa Barbara, CA 93106-9510, USA
E-mail: javier@chem.ucsb.edu
Homepage: http://www.chem.ucsb.edu/~read
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300832.
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L. I. Palmer, G. K. Veits, J. Read de Alaniz
SHORT COMMUNICATION
Several procedures have been developed to facilitate the within minutes. A notable exception was p-toluenesulfonic
rearrangement of substituted 4-hydroxycyclopentenones, acid, which showed the fused cyclopentenone in roughly
generally en route to prostaglandins (Figure 2).[4b] The mi- 50% conversion after 24 h. We were pleased to find that the
gration of the alcohol functional group can occur in an in- acidic ion-exchange resin Amberlyst®15 could be used to
tramolecular fashion (Figure 2, a)[7] or through a hy- carry out the same transformation in a cleaner and more
dration–dehydration sequence (Figure 2, b).[8] Wu and co- efficient manner; treatment of 1 with acidic Amberlyst®15
workers recently took advantage of a two-step sequence, provided fused bicycle 2 in excellent yield (Table 1, entry 8).
nucleophilic addition of a tethered alcohol followed by eli-
mination of water, to gain access to fused oxabicycles from Table 1. Optimization studies for the scaffold rearrangement.[a]
the corresponding 4-hydroxycyclopentenones (Figure 2,
c).[9] We sought to develop a new strategy that would pro-
ceed through the spirocyclic ether and upon combination
with our previous methodology would offer straightforward
access to two classes of oxabicycles from the same furyl-
carbinol starting material.
Entry
Reagent (mol-%)[b]
Yield [%] trans-1/cis-1/2[c]
1
2
3
4
5
6
7
8
basic alumina (na)[d]
ZnCl2 (20)
HCl (20)
H2SO4 (20)
CSA (20)
45:45:0
89:5:0
57:3:0
decomposition
66:9:0
41:3:36
45:45:0
0:0:91
pTSA (20)
PMA (20)
Amberlyst® 15 (na)[d]
[a] Reactions were performed in toluene at 60 °C. [b] CSA = cam-
phorsulfonic acid, pTSA = p-toluenesulfonic acid, PMA = poly-
phosphomolybdic acid. [c] Determined by analysis of the reaction
1
mixture by H NMR spectroscopy. [d] n.a.: not applicable.
Importantly, this skeletal rearrangement is general and
can be used to efficiently prepare the fused oxabicycles di-
rectly from their spirocyclic precursors in high yield
(Table 2). All substrates subjected to the reaction conditions
behaved accordingly. The rearrangement was extremely
clean for electron-rich, electron-poor, and bulky-substituted
cyclopentenones (i.e., 5, 6, 7–9) but slower and slightly
lower yielding if the ether oxygen atom was substituted with
a gem-dimethyl group (i.e., 12 and 13). We were thrilled to
discover that treatment of a mixture of diastereomers at the
Figure 2. Migration of alcohol functional group.
Results and Discussion
Given the mechanistic possibility that spirocyclic ether 1 γ position of the spirocyclic ether to the reaction conditions
could be a precursor to the more thermodynamically stable resulted in the formation of a single diastereomer of the
oxabicyclic cyclopentenone 2, we decided to further investi- bicyclic ether (i.e., 14 and 15). An anti relationship, corre-
gate this relationship (Table 1). Initially, we attempted the sponding to the more thermodynamically stable product,
conversion between the two bicycles by using reaction con- was confirmed by NOE experiments.[10] Interestingly, for
ditions previously described by Wu et al. (ZnCl2 in re- isopropyl substrate 16, only a 7:1 ratio was achieved. The
fluxing aqueous 1,2-dimethoxyethane).[9] No change to the molecular rearrangement allowed efficient access to chryco-
spirocycle was observed, and 1 was recovered from the reac- rin (10), a natural product with plant growth inhibitor
tion in good yield with little to no decomposition. Treat- properties, isolated from Chrysanthemum coranarium by
ment of the spirocycle with basic alumina resulted in com- Tada and Chiba.[9,11] Moreover, the skeletal rearrangement
plete erosion of the trans selectivity through epimerization; demonstrated that spirocyclic ethers are a viable intermedi-
however, no desired rearrangement was observed. Interest- ate in the synthesis of oxabicyclic cyclopentenones from an
ingly, other bases such as 4-(dimethylamino)pyridine, acid-catalyzed cascade rearrangement of α-furylcarbinols.
Hünig’s base, cesium carbonate, sodium carbonate, and so-
From a mechanistic and synthetic point of view, it is
dium phosphates resulted in only recovered starting mate- interesting that only a single diastereomer was isolated in
rial. On the basis of these experiments, we further examined the case of substituted products 14 and 15 from a 2:1 dia-
the use of other acids (Table 1, entries 3–7), which also re- stereomeric mixture of the starting materials. It could be
sulted in epimerization of the trans-substituted spirocycle to considered that the skeletal rearrangement follows a step-
a mixture of trans and cis isomers to varying degrees along wise pathway (Figure 3) that allows the interconversion of
with other unidentified minor reaction components. Treat- intermediates to thermodynamically favored cyclo-
ment of 1 with sulfuric acid resulted in its decomposition pentenone framework 2. In acidic media, protonation of
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Rapid Synthesis of Fused Oxabicycles
Table 2. Substrate studies for the scaffold rearrangement.[a]
Figure 3. Possible mechanism of the skeletal rearrangement and
proposed source of selectivity.
Figure 4. ORTEP structure of fused cyclopentenone 14. Ellipsoids
drawn at 30% probability.
Amberlyst®15 concurrently (Table 3, entry 3) gave fused cy-
clopentenone 2 in only 34% yield. On the basis of Wu’s
one-pot protocol in which water was found to be critical to
obtain good yields,[9] we tested if water would have a similar
effect on the one-pot reaction in Table 3. Unfortunately, the
addition of water as a co-solvent (1:1, H2O/PhMe) gave
similar results. During the course of these reactions, spi-
rocyclic ether 1 was observed, along with a number of by-
products. These results suggest that our one-pot reactions
go through the formation of 1, which is presumably respon-
sible for the low yields. This is not entirely surprising, be-
cause in our previous studies on the formation of 1 from
the corresponding furylcarbinol, extensive optimization of
the reaction conditions was required to achieve good yields.
Although our protocol allows direct access to fused cyclo-
pentenone 2 directly from furylcarbinol 17, the described
[a] Yield of isolated product. [b] Isolated as a single diastereomer.
[c] A 7:1 ratio of diastereomers was obtained.
spirocyclic ether 1 in combination with the acidity of the
(here, benzylic) proton in I and the proximity of the carb-
onyl group leads to cleavage of the ether to give alcohol II.
This extremely reactive species would close rapidly through
attack of the primary alcohol to give intermediate III,
which upon tautomerization yields thermodynamically
favored, fused cyclopentenone 2.
If a secondary alcohol is used, as in the case of products
14 to 16, a secondary alcohol substituent in the equatorial
position during ring closure minimizes unfavorable steric
interactions (Figure 3). The possibility of introducing 1,3-
diaxial interactions is illustrated clearly in the obtained
crystal structure of product 14 (Figure 4).[12]
Table 3. Testing a one-pot procedure.
Notably, we can access the desired fused cyclopentenone
framework directly from furfural-derived starting materials
(Table 3).[9] Treatment of furylcarbinol 17 with Am-
berlyst®15 and heating in toluene at 60 °C gave the desired
product in 39% yield (Table 3, entry 1). Heating the furyl-
carbinol at 100 °C followed by treatment with Am-
berlyst®15 at 60 °C produced the product in only 16% yield.
We were surprised to discover that treatment of furylcarb-
inol 17 with Dy(OTf)3 (Tf = trifluoromethylsulfonyl) and
Entry
Catalyst
Yield [%]
1
2
3
Amberlyst®15
39
16
34
100 °C, then Amberlyst®15
Dy(OTf)3 (5 mol-%) + Amberlyst®15
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L. I. Palmer, G. K. Veits, J. Read de Alaniz
SHORT COMMUNICATION
[2]
[3]
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Conclusions
In conclusion, we have demonstrated the operationally
simple conversion of spirocyclic ethers into fused bicyclic
ethers through an acid-catalyzed isomerization. This trans-
formation provides direct access to fused oxabicycles, which
are important intermediates in the total synthesis of numer-
ous biologically active molecules. We believe this approach
to fused oxabicycles is attractive, because it demonstrates
the versatile nature of using renewable resources to build
molecular diversity, and as such, current efforts are focused
on extending this methodology to include industrially im-
portant transformations and to utilizing our products as
substrates for further synthetic manipulations.
[5]
Experimental Section
General Procedure for the Synthesis of Fused Bicyclic Ethers: Oxa-
spirocycle 1 (0.05 mmol) was stirred as a solution in toluene
(1.2 mL) at 23 °C and treated with Amberlyst®15 (20 mg). The re-
action flask was immediately placed in an oil bath preheated to
60 °C. Upon completion of the reaction (as evident by TLC), the
reaction mixture was cooled to room temperature and filtered
through cotton and eluted with ethyl acetate. The combined or-
ganic layer was concentrated in vacuo to afford oxabicycle 2.
[6]
[7]
a) G. K. Veits, D. R. Wenz, J. Read de Alaniz, Angew. Chem.
2010, 122, 9674–9677; Angew. Chem. Int. Ed. 2010, 49, 9484–
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c) L. I. Palmer, J. Read de Alaniz, Org. Lett. 2013, 15, 476–479;
d) D. R. Wenz, J. Read de Alaniz, Org. Lett. 2013, 15, 3250–
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Supporting Information (see footnote on the first page of this arti-
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[9] For studies on furylcarbinols to access fused bicycles, see: a)
B.-L. Yin, Y. Wu, Y.-L. Wu, J. Chem. Soc. Perkin Trans. 1 2002,
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[10] On the basis of the NOE and crystal structure of 14, the stereo-
chemistry of 15 and 16 were assigned by analogy.
[11] M. Tada, K. Chiba, Agric. Biol. Chem. 1984, 48, 1367–1369.
[12] See the Supporting Information. CCDC-931233 contains the
supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Received: June 5, 2013
Acknowledgments
This work was supported by the National Science Foundation
(NSF), USA (CAREER Award CHE-1057180) and the University
of California, Santa Barbara (UCSB). The authors kindly acknow-
ledge additional support provided by UCSB Graduate Research
Mentorship Program Fellowship (to G. K. V.) and also thank Dr.
Guang Wu (UCSB) for X-ray analysis.
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O. Machhammer, J. Schwartze, M. Volland, Chem. Eng. Tech-
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Published Online: August 26, 2013
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