Sequential Ketene Generation from Dioxane-4,6-dione-keto-dioxinones for the Synthesis of Terpenoid Resorcylates

Article abstract of DOI:10.1021/acs.orglett.6b00533

Trapping of the ketene generated from the thermolysis of 2-methyl-2-phenyl-1,3-dioxane-4,6-dione-keto-dioxinone at 50°C with primary, secondary, or tertiary alcohols gave the corresponding dioxinone β-keto-esters in good yield under neutral conditions. Th

Full text of DOI:10.1021/acs.orglett.6b00533

Letter
pubs.acs.org/OrgLett
Sequential Ketene Generation from Dioxane-4,6-dione-keto-
dioxinones for the Synthesis of Terpenoid Resorcylates
Daniel C. Elliott, Tsz-Kan Ma, Aymane Selmani, Rosa Cookson, Philip J. Parsons,
and Anthony G. M. Barrett*
Department of Chemistry, Imperial College, London, SW7 2AZ, U.K.
*
S Supporting Information
ABSTRACT: Trapping of the ketene generated from the thermolysis of 2-methyl-2-phenyl-1,3-dioxane-4,6-dione-keto-
dioxinone at 50 °C with primary, secondary, or tertiary alcohols gave the corresponding dioxinone β-keto-esters in good yield
under neutral conditions. These intermediates were converted by palladium(0)-catalyzed decarboxylative allyl migration and
aromatization into the corresponding β-resorcylates. These transformations were applied to the syntheses of the natural products
(
±)-cannabiorcichromenic and (±)-daurichromenic acid.
he 6-alkyl-2,4-dihydroxybenzoic acid or β-resorcylic acid
resorcylates in which the allyl moiety was transferred
T
moiety is a structural entity embedded in diverse
specifically to the arene C-3 position giving the allyl-resorcylate
3 (Type I). This sequence provided diverse meroterpenoids in
two steps. Alternatively, reaction of C-acylated dioxinone β-
keto-esters, derived from allyl ester 1a with a palladium(0)
catalyst and morpholine followed by ketene trapping with an
alcohol and subsequent aromatization, gave resorcylates 5
2
biologically active natural products. Many members of the
resorcylates show useful biological effects and have complex
and intriguing molecular structures. As such, resorcylates
remain attractive targets for both total synthesis studies and
as possible drug candidates.
(
Type II). We have employed this second process for the total
Over the past decade our group has developed a genera1l
synthesis of many biologically important resorcylic acid
strategy for the synthesis of β-resorcylates (Scheme 1).
3
lactones.
Palladium-catalyzed decarboxylative allylic migration and
aromatization of dioxinone β-keto-esters 1 provided β-
The use of dioxinone β-keto-esters 1 is fundamental to our
strategy for the synthesis of meroterpenoids. Previously we
have applied three different reactions to synthesize these key
intermediates 1 (Scheme 2): (1) Claisen condensation of the
lithium enolate 9 with β-keto acid derivatives (8a or 8b)
Scheme 1. Biomimetic Strategies for the Synthesis of β-
Resorcylates
(
pathway A); (2) condensation of the dienolate 11 with
imidazoyl carbamates 10 (pathway B); and (3) bismuth(III)
triflate catalyzed Muikayama-type reactions of acyl chlorides 8b
with enol silane 12 (pathway C).
Although we have demonstrated these methods are syntheti-
cally useful, they have limitations. Each method employed
excess enolate or enol silane relative to the acyl donor. After
workup, separation of the β-keto-ester from residual dioxinone
or keto-dioxinone usually required chromatography, which is
inappropriate when the reaction is scaled up. In addition, these
reactions resemble more classical procedures to construct 1,3-
dicarbonyl systems (i.e., ketone enolate acylations); as such,
4
yields obtained are often modest and can be capricious. Others
Received: February 25, 2016
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00533
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Organic Letters
Letter
Scheme 2. Literature Methods for the Synthesis of
Dioxinone β-Keto-esters
Herein we report the use of dioxane-4,6-dione-keto-
dioxinones 16a and 16b as synthetic equivalents for double-
dioxinones (Scheme 4). Mindful of a possible regioselectivity
Scheme 4. Thermolysis of Dioxane-4,6-dione-keto-
dioxinones
problem in the key initial monoketene generation reaction, we
considered that, if necessary, we could modulate the reactivity
by modification of the Meldrum’s acid moiety. The thermally
1
induced retro-Diels−Alder reaction of compound 16b (R =
2
Me, R = Ph) should form ketene 14 faster than ketene 17
because of arene π-delocalization into the O−CO σ* orbital.
This has precedent with simple dioxinone thermolysis
9
reactions.
Dioxanedione-dioxinones 16a and 16b were prepared in two
steps from commercially available dioxinone 18. Dioxinone acid
1
9
9 was prepared in 91% yield by trapping of the lithium enolate
with carbon dioxide. A DCC coupling reaction of dioxinone
have reported similar findings with enolates derived from
dioxinones in Claisen condensation reactions.
acid 19 with Meldrum’s acid 20a or 20b gave adducts 16a and
6b respectively. For our initial experiments, we screened the
5
1
In light of our continued interest in the parallel synthesis of
increasingly complex β-resoryclates in programs of medicinal
chemistry and for scale-up use, we sought to remedy these
limitations in the reaction sequence. In this letter we report a
new and more reliable method for the synthesis of dioxinone β-
keto esters based on the reaction of an alcohol with a
dioxanedione-dioxinone. This procedure is operationally
simple, mild, and versatile.
reaction of adducts 16a and 16b with farnesol (Scheme 5).
Scheme 5. Synthesis of Dioxane-4,6-dione-keto-dioxinones
and Reaction with Farnesol
At the outset of this work, the only alternative method
reported for construction of dioxinone β-keto-esters was by
6
Kiegiel and co-workers (Scheme 3). Under controlled
conditions, they successfully converted double-dioxinone 13
into the corresponding tert-butyl β-keto-ester 15 in 57% yield.
Scheme 3. Kiegiel’s Reaction of tert-Butanol with Double-
Dioxinone 15
Reaction of dioxanedione-dioxinone 16a with farnesol in
toluene at 70 °C was not regioselective and gave keto ester 1i in
only 29% yield. On the other hand, reaction of dioxanedione-
dioxinone 16b gave keto ester 1i in 87% yield. We extended
this reaction to a range of allylic alcohols (Scheme 6), and in all
cases monoesterification was effective for primary, secondary,
and tertiary allylic alcohols at 50 °C.
With a series of keto esters 1 available, we examined their
conversion to the corresponding resorcylates 3 (Scheme 7).
2a−c,f−h
Following our earlier publications,
we screened the
In Kiegiel’s report, double-dioxinone 13 was prepared from
ketene. Since the preparation and handling of ketene (from the
high temperature pyrolysis of acetone at or above 700 °C) is an
allylic rearrangement and aromatization sequence by allowing
the keto esters 1b to 1l to react with Pd(PPh ) followed by
3
4
aromatization with cesium carbonate or silica gel. In general, we
found this catalyst system gave low yields (<20%) and was not
compatible with substrates bearing an endocyclic alkene, which
gave only intractable mixtures. After screening a range of
catalysts, we found that Pd dba in the presence of tri-2-
7
inconvenient process, and there was no information available
on whether or not it was possible to effect monoaddition of
8
primary or secondary alcohols to bis-dioxinone 13, we did not
investigate its use for the preparation of compound 1.
2
3
B
DOI: 10.1021/acs.orglett.6b00533
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Letter
Scheme 6. Reaction of Allylic Alcohols with Dioxanedione-
dioxinone 16b
Scheme 7. Conversion of Dioxinone Keto Esters 1b−1l to
a
a
Resorcylates 3b−3l
a
The remaining product could not be isolated from the crude reaction
mixture.
a
Starting material recovered.
furylphosphine gave acceptable conversions with most
substrates 1.
For substrates that underwent reaction, the rearrangement of
Scheme 8. Total Synthesis of (± )-Cannabiorcichromenic
and (± )-Daurichromenic Acids 22a and 22b
1
0
acylated keto esters 1 to produce the diketo-ester intermediates
2
was complete within 1 h but these were not isolated but
directly converted into the corresponding resorcylates. These
aromatization reactions were more rapid (1 h for completion)
using the soluble cesium acetate in isopropanol rather than
cesium carbonate or silica gel. Steroid 1l did not undergo
reaction, possibly due to the steric hindrance imparted by the
C-19 methyl group.
Finally, we applied the reaction to the total syntheses of the
11
antibiotic (±)-cannabiorcichromenic acid (22a) and the anti-
11,12
HIV agent (±)-daurichromenic acid
(22b) (Scheme 8).
For the elaboration of the 2H-chromene ring system, we
examined a number of oxidative cyclization conditions reported
to be effective for o-allylic phenols. Reaction of phenol 3h or 3i
with DDQ or potassium dichromate in benzene gave the
derived resorcylates and meroterpenoids. The application of
this new methodology to the total synthesis and medicinal
chemistry of biologically relevant resorcylates is ongoing in our
laboratory.
13
corresponding chromene but in low yield (<30%). On the
other hand, the palladium-catalyzed aerobic oxidative cycliza-
tion reaction reported by Larock and co-workers was highly
1
4
ASSOCIATED CONTENT
Supporting Information
effective. Thus, treatment of resorcylate 3h or 3i with
■
15
*
S
palladium(II) acetate under 1 atm of oxygen gave chromenes
1a and 21b in 68% and 63% yields, respectively.
2
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00533.
Saponification with potassium hydroxide in THF gave the
desired (±)-cannabiorcichromenic and (±)-daurichromenic
acids 22a and 22b. The spectral properties displayed by both
1
13
Spectral data for all new compounds (PDF)
X-ray data and structure of 3h (PDF)
Crystallographic data for 3h (CIF)
Experimental procedures (PDF)
compounds ( H, C NMR and HRMS) were in excellent
16
agreement with data reported for the natural products.
In conclusion, we have developed a simple and reliable
procedure for the synthesis of dioxinone β-keto-esters and
C
DOI: 10.1021/acs.orglett.6b00533
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Organic Letters
Letter
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: agmb@ic.ac.uk.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the European Research Council for support (Grant
Agreement Number 267281).
■
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DOI: 10.1021/acs.orglett.6b00533
Org. Lett. XXXX, XXX, XXX−XXX