Benzannulated 6,5-Spiroketals from Donor-Acceptor Cyclopropanes

Article abstract of DOI:10.1021/acs.orglett.9b00878

A rapid and facile synthesis of benzannulated 6,5-spiroketals from vinyl 1,1-diacylcyclopropanes is reported. The method utilizes mild reaction conditions with good to excellent yields and high diastereoselectivity. This methodology was then used to construct the core of berkelic acid.

Full text of DOI:10.1021/acs.orglett.9b00878

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Benzannulated 6,5-Spiroketals from Donor−Acceptor
Cyclopropanes
Sinan Gai, Nigel T. Lucas, and Bill C. Hawkins*
Department of Chemistry, University of Otago, Dunedin 9054, New Zealand
*
S Supporting Information
ABSTRACT: A rapid and facile synthesis of benzannulated
,5-spiroketals from vinyl 1,1-diacylcyclopropanes is reported.
6
The method utilizes mild reaction conditions with good to
excellent yields and high diastereoselectivity. This method-
ology was then used to construct the core of berkelic acid.
umerous biologically active natural products, which have
underwent a standard acid catalyzed spiroketalization to afford
13a
N
been isolated from both terrestrial and marine
a 5,5-spiroketal.
The most recent involved reduction of
1
organisms, have been found to contain the spiroketal motif.
cyclopropyl esters to their corresponding primary alcohols
It is within this class of molecules that the relatively rare
followed by oxidation with hypervalent iodine complexes
2
3
13b
benzannulated spiroketals, such as the chaetoquadrins (1),
(Scheme 1).
The presumed cyclopropyl aldehyde inter-
4
5
berkelic acid (2), and pinnatifinosides (3), are found (Figure
). Beyond the standard acid catalyzed cyclization of a
1
Scheme 1. Werz et al. Described the Reduction of
Cyclopropyl Esters and Subsequent Oxidation with
Hypervalent Iodine to Provide Spiroketals
mediate could then be treated in situ with a soft Lewis acid to
facilitate ring expansion to the spirocyclic enol ether 5. This
study included the synthesis of one unsubstituted benzannu-
lated spiroketal which was obtained in a 35% yield from the
corresponding cyclopropyl ester. While elegant, the reaction
conditions limit substrate scope and the oxidation state
manipulations, requiring stoichiometric amounts of both
reductant and oxidant, are viewed as less than ideal.
We speculated that the treatment of vinylcyclopropane 6
with palladium(0) would not only isomerize the allyl ether to
the labile vinyl ether, leading to the phenolate anion, but also
facilitate cyclopropane ring opening via oxidative addition to
produce the intermediate zwitterion 7 (Scheme 2). The
oxygen anion of intermediate lactol 7 could then attack the π-
allyl complex, eventually leading to benzannulated 5,6-
spiroketals of the general structure 8.
Figure 1. Representative benzannulated spiroketal containing natural
products.
14
dihydroxy ketone (or equivalent), current methods used to
synthesize this moiety include transition-metal-catalyzed
6
7
spiroketalizations, 8cycloaddition strategies, and oxidative
radical cyclizations.
To examine this concept, the β-keto ester 10a was prepared
from 2-hydroxyacetophenone 9 in four steps using adapted
Donor−acceptor cyclopropanes have been utilized exten-
sively in the literature to gain access to biologically active
15
9
literature procedures (Scheme 3). Treatment of the β-keto
ester 10a with 1,4-dibromo-trans-2-butene and potassium
carbonate provided the vinylcyclopropyl adduct 6a as a
2:2:1:1 mixture of diastereomers. The vinyl cyclopropane
was found to be unstable to purification by silica gel column
scaffolds, including numerous natural products. Their unique
reactivity allows for a rapid increase in structural complexity
1
0
through various reaction processes including ring opening,
cycloadditions, and rearrangements/ring expansions.
1
1
6c,12
However, only two reports using a ring expansion of donor−
acceptor cyclopropanes to access spiroketals have appeared in
1
3
the literature. The first used a donor−acceptor cyclopropane
Received: March 12, 2019
to eventually make a dihydroxyketone which subsequently
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00878
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Synthetic Strategy for the Formation of
Benzannulated Spiroketals
Scheme 4. Synthesis of Benzannulated 6,5-Spiroketals;
ORTEP Diagrams of Both Isomers of 8n
Scheme 3. Synthesis of Benzannulated 6,5-Spiroketals 8a
and Crystal Structure of Diastereomers 8ai (Left) and 8aii
(
Right)
portion of the substrate was examined first. Electron-rich
substituents were well tolerated (8b and 8c), as well as
relatively neutral 8f and 8g and relatively electron-poor
systems 8e. Notably, under the spiroketalization reaction
conditions no dehalogenation was observed, thereby preserv-
ing the additional functional group handle. Changing the
substrate to a 1,3-diketone resulted, in general, in a slight
decrease in yield. As for the β-keto ester substrate, both the tri-
and tetrasubstituted aromatic systems with varying electronics
were also well tolerated with negligible differences in isolated
yield with the exception of the dibromo analog 8m, which
proceeded in a slightly lower yield (44%, over two steps).
Removal of the methyl group in the benzylic position had no
observable effect on diastereoselectivity (8n). Regardless of the
substitution pattern and functional groups present, an excellent
level of diastereoselectivity was observed in all cases, with
complete control of the relative stereochemistry at all
stereocenters except at the vinylic position, where no control
at all was achieved.
chromatography. However, treatment of the crude residue
containing predominately 6a with Pd(PPh ) (5 mol %) and
3
4
K CO in ethanol for 16 h at room temperature smoothly
2
3
provided the benzannulated 6,5-spiroketal 8a as a 1:1 mixture
1
of diastereomers, as indicated by analysis of the H NMR
16
spectrum of the reaction mixture; the diastereomers were
readily separated by chromatography. Both isomers are a result
of the anomeric effect with the relative stereochemistry set
except at the vinyl group. This assignment was confirmed by
single crystal X-ray structures of both isomers (Scheme 3).
Increasing the catalyst loading to 10 mol % had no
significant impact on isolated yield; however, decreasing the
catalyst loading to 2.5 mol % resulted in a lower isolated yield
16
and required longer reaction times to reach completion. An
alternative source of Pd(0), tris(dibenzylideneacetone)-
dipalladium, was also trialed; however, lower yields were
observed. Ethanol was found to be the solvent which provided
the highest yield, although other solvents such as THF could
be used. Notably, when methanol was used transesterification
was observed to provide the corresponding methyl ester.
With a procedure developed for the synthesis of
benzannulated 6,5-spiroketals, we next examined the substrate
scope (Scheme 4). Variation in the substitution of the aromatic
In order to provide insight into the mechanism and features
controlling the stereochemical outcome, a diastereomerically
pure sample of 8ni was subjected to the established reaction
conditions (Scheme 5). After stirring at room temperature for
16 h a 1:1 mixture of the diastereomers (8ni/ii) was obtained,
thereby indicating the reaction is under thermodynamic
control.
Further examination of the reaction by shortening the
reaction time from 16 h to 30 min led to the isolation of the
B
DOI: 10.1021/acs.orglett.9b00878
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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Scheme 5. Treatment of Benzannulated Spiroketal 8ni to
the Established Spiroketalization Reaction Conditions
Provided a 1:1 Mixture of Diastereomers (8ni/ii)
Scheme 7. Synthesis of the Berkelic Acid Core and ORTEP
Diagram of 17bi
dihydrofuran 13iB and traces of 15iB (Scheme 6). These
compounds are thought to arise from ring closure of the
Scheme 6. Proposed Mechanism
In conclusion, we have disclosed a novel and highly efficient
method to access benzannulated 6,5-spiroketals. The reaction
proceeds at ambient temperatures to provide a diverse array of
functionalized systems including the entire scaffold of berkelic
acid. Current efforts are focused toward applying this
methodology to the synthesis of benzannulated spiroketal
containing natural products.
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00878.
Experimental procedures; characterization data and
NMR spectra; crystallographic data for X-ray crystal
structures of 8ai−ii, 8ni−ii, and 17bi−ii (PDF)
Accession Codes
CCDC 1901377−1901382 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
enolates 12i and 14i, respectively. Treatment of the mixture of
dihydrofurans under the standard reaction conditions provided
the expected benzannulated spiroketals 8i. Notably, analysis of
1
the H NMR spectra of aliquots of the reaction mixture at 3
and 8 h time points showed no evidence of any other
intermediate, simply a varying ratio of 13iB/15iB to 8i. It
remains unclear if the oxidative addition to the vinyl
cyclopropane occurs prior to, or after, deallylation. Regardless,
the conversion of dihydrofurans 13iB and 15iB to the
spiroketals 8i provides support for the proposed mechanism
outlined above.
AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: bhawkins@chemistry.otago.ac.nz.
ORCID
With a clearer picture of substrate scope and mechanism
established, attention was turned to applying the newly
developed methodology to the construction of the tetracyclic
Nigel T. Lucas: 0000-0002-4944-9875
Bill C. Hawkins: 0000-0001-7677-4422
Notes
16
core of berkelic acid. Treatment of the benzopyran 16a, with
,4-dibromobut-2-ene in the presence of potassium carbonate,
The authors declare no competing financial interest.
1
provided the corresponding vinyl cyclopropane as an
inconsequential 1:1:1:1 mixture of diastereomers (Scheme
ACKNOWLEDGMENTS
■
7
). The crude residue was subjected to the standard reaction
conditions to afford the entire scaffold of berkelic acid 17a as a
:1 mixture of diastereoisomers in excellent yield.
We acknowledge the University of Otago for a Research grant
(UORG). S.G. gratefully acknowledges the University of
Otago for the provision of a PhD scholarship.
1
C
DOI: 10.1021/acs.orglett.9b00878
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(
14) Smith, R. J.; Nhu, D.; Clark, M. R.; Gai, S.; Lucas, N. T.;
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DOI: 10.1021/acs.orglett.9b00878
Org. Lett. XXXX, XXX, XXX−XXX