Chemoselective and Diastereoconvergent Cu(II)-Catalyzed Aerobic Endoperoxidation of Polycarbonyls

Article abstract of DOI:10.1021/acs.orglett.7b01225

The diastereoconvergent synthesis of spirocyclic endoperoxides using a Meldrum's acid scaffold has been accomplished by employing readily available feedstock chemicals. Site selective C-H oxidation of the bis(β-dicarbonyl) substrates was performed using e

Full text of DOI:10.1021/acs.orglett.7b01225

Letter
pubs.acs.org/OrgLett
Chemoselective and Diastereoconvergent Cu(II)-Catalyzed Aerobic
Endoperoxidation of Polycarbonyls
James Giarrusso, Dung T. Do, and Jeffrey S. Johnson*
Department of Chemistry, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
S
* Supporting Information
ABSTRACT: The diastereoconvergent synthesis of spirocyclic
endoperoxides using a Meldrum’s acid scaffold has been
accomplished by employing readily available feedstock chemicals.
Site selective C−H oxidation of the bis(β-dicarbonyl) substrates
was performed using elemental oxygen as the stoichiometric
oxidant and a commercial Cu(II) catalyst. Sequential hydro-
genolysis and ionic reduction of these endoperoxides provided
fully substituted tetrahydrofurans in high yields and diastereoselectivity.
yclic peroxides exhibit a variety of therapeutic properties.1
Perhaps the most well-known naturally occurring endoper-
Scheme 1. Divergent Modes of Cu(II)-Catalyzed Aerobic
Oxidations of β-Dicarbonyl Compounds
C
oxide is the antimalarial artemisinin isolated from the leaves of
Artemisia annua.2−5 The endoperoxide motif is located in
numerous other natural products and exhibits a wide variety of
bioactivities including anticancer, antitumor, and antiviral
properties.6 The formation of endoperoxides is commonly
accomplished by oxidations employing molecular oxygen.7,8
Oxidations of β-dicarbonyls to generate peroxides9 and
endoperoxides10−16 are also precedented, typically via oxidation
of an enolate. Previous work involving enolate oxidations showed
that subjecting α-substituted β-dicarbonyls 1 to catalytic Cu(II)
under aerobic conditions resulted in α-keto ester 2 via oxidative
deacylation (Scheme 1a).17−20 Attempts to extend this oxidative
cleavage to substituted Meldrum’s acids 3 yielded the
corresponding hydroperoxide 4 instead of the expected α-keto
acid (Scheme 1b).21 An important feature of that work was the
compatibility of the reaction conditions with oxidation-sensitive
functionality such as alkenes and alkynes. This finding enabled
downstream transformations that utilized the elevated oxidation
state of the enolate functionalization.
We were interested in testing the notion that other
transformations could be developed under this general paradigm
whereby molecular complexity is generated via straightforward
carbon skeleton constructions followed by redox reactions that
create the functional and stereochemical features.22 In the ideal
scenario, the oxidation and reduction operations would be
mediated by green oxidants like O223 and H2.24 A polyfunctional
substrate such as keto triester 5 would permit us to test the
relative rates of the previously validated deacylation and
hydroperoxidation pathways. This letter provides details of a
straightforward sequence for the de novo creation of highly
substituted tetrahydrofurans that relies on an enabling chemo-
selective Cu(II)-catalyzed aerobic oxidation and sequential
reductions of the resultant endoperoxides (Scheme 1c).
At the core of our reaction design was an interest in
straightforward carbon skeleton buildup. The required Michael
adducts 5 were obtained by treating Meldrum’s acid alkylidene 7
Received: April 23, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01225
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
with the sodium enolate of ethyl acetoacetate (8).25 Michael
adducts 5 were chromatographically unstable, owing to a facile
retro-Michael fragmentation on silica. To circumvent this
instability, the unpurified adducts were used directly in the
catalyzed oxidation step. Prior work validated that oxidation at
either the Meldrum’s acid C−H methine21 or β-keto ester C−H
methine17 is possible; therefore, an open question was the
possibility and degree of site selectivity. In the event, under
aerobic copper catalysis, we observed complete site selectivity for
Meldrum’s acid oxidation over the acetoacetate moiety. The
resultant hydroperoxide was readily trapped by the pendant
ketone electrophile, furnishing endoperoxides 6 in moderate
yields (Table 1). The process was amenable to both alkyl- and
Scheme 2. Proposed Rationale for Diastereoselectivity
Table 1. Michael Addition and Endoperoxidation of
a
Meldrum’s Acid Derivatives: Substrate Scope
ultimate thermodynamic preference for the bis(equatorial)
disposition of the C4 and C5 substituents in the hemiketal
would drive the final observed preference.
Due to their reactive nature, organic peroxides often require
special consideration when handling.26 Meldrum’s acid hydro-
peroxides (e.g., 4) decompose rapidly at a low onset temperature
upon subjection to thermogravimetric analysis;21 however, this
phenomenon was not seen with the related endoperoxides 6, 9,
and 10. These compounds are bench-stable and exhibit
significant thermal stability (see the Supporting Information
(SI)).
Endoperoxides 6 undergo catalyzed hydrogenolysis27 yielding
spirocyclic hemiketals 12 in good yields (Table 2). Both alkyl and
a
Table 2. Hydrogenolysis of Endoperoxides: Substrate Scope
a
1.15 equiv of NaH, 1.2 equiv of dicarbonyl, [7]0 = 0.35 M.
Cu(NO3)2·3H2O (20 mol %), 1 atm O2, [5]0 = 0.1 M, 0 °C to rt.
b
c
Isolated yields over two steps. Diastereomeric ratio (dr) reported
d
after silica gel chromatography. 2,4-pentanedione used in place of 8.
e
N,N-dimethylbarbituric acid alkylidene used in place of 7.
aryl-substituted Meldrum’s acid derivatives (6a−6e), tolerating
ortho-substituted aryl groups 6f, albeit with diminished yields.
Modest diastereoselectivity was observed in the local desymmet-
rization product 9 of 2,4-pentanedione-substituted Michael
adduct. N-Methylated barbituric acid could be substituted for the
Meldrum’s acid, with no loss in efficiency of the oxidation.
Michael adducts 5 are formed with negligible diastereocontrol,
while the derived endoperoxides 6 are isolated with high
diastereomeric purity as a result of apparent stereochemical
convergence. Scheme 2 depicts a proposal for this stereochemical
correction. Hemiketalization is presumed to be reversible and in
the open chain form the β-keto ester engenders considerable
acidity to the methine C−H bond. Enolization would facilitate
interconversion of the diastereomeric open chain forms. An
a
b
100 mg Pd/C per mmol 6, 1 atm H2, [6]0 = 0.1 M. Isolated yield.
c
Diastereomer ratio at the acetal center.
aryl substrates tolerated these conditions, albeit with some
variability in diastereomer ratio at the anomeric center. An
endoperoxide with an electron deficient arene (6g) was not
tolerated in the hydrogenolysis; those trials resulted in substrate
decomposition. The hydrogenolysis was also amenable to the
acyl and barbituric acid substrates 9 and 10, providing the
respective lactol products 13 and 14 in high yields.
B
DOI: 10.1021/acs.orglett.7b01225
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Subsequent Lewis acid mediated ionic reduction28,29 of
hemiketals 12 furnished spirocyclic tetrahydrofurans 15 in high
diastereoselectivity in most cases (Table 3). The presumed
Experimental procedures and spectroscopic data for all
new compounds; general experimental procedures; 1D
NMR data; HR ESI-MS and IR data of new compounds
(PDF)
a
Table 3. Ionic Reduction of Hemiketals: Substrate Scope
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jsj@unc.edu
ORCID
Jeffrey S. Johnson: 0000-0001-8882-9881
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The project described was supported by Awards NSF-CHE
1402917 and NSF-CHE 1665008. We thank Professor Luiz Dias
(UNICAMP) for useful discussions. D.T.D. acknowledges a
Vietnam Education Foundation Fellowship. X-ray crystallog-
raphy was performed by Dr. Peter White (UNC Chapel Hill).
REFERENCES
■
(1) Dembitsky, V. M. Eur. J. Med. Chem. 2008, 43, 223.
(2) Klayman, D. L.; Lin, A. J.; Acton, N.; Scovill, J. P.; Hoch, J. M.;
Milhous, W. K.; Theoharides, A. D.; Dobek, A. S. J. Nat. Prod. 1984, 47,
715.
(3) Krishna, S.; Bustamante, L.; Haynes, R. K.; Staines, H. M. Trends
Pharmacol. Sci. 2008, 29, 520.
(4) White, N. J. Science 2008, 320, 330.
(5) Pandey, A. V.; Tekwani, B. L.; Singh, R. L.; Chauhan, V. S. J. Biol.
Chem. 1999, 274, 19383.
(6) Bu, M.; Yang, B.; Hu, L. Curr. Med. Chem. 2016, 23, 383.
(7) Terent’ev, A. O.; Borisov, D. A.; Vil’, V. A.; Dembitsky, V. M.
Beilstein J. Org. Chem. 2014, 10, 34.
(8) Chung, A.; Miner, M. R.; Richert, K. J.; Rieder, C. J.; Woerpel, K. A.
J. Org. Chem. 2015, 80, 266.
a
BF3·OEt2 (5.34 equiv), Et3SiH (10 equiv), [12]0 = 0.1 M, 0 °C, 30
b
min. Isolated yield.
(9) Rahman, T.; Nishino, H. Org. Lett. 2003, 5, 2887.
(10) Novkovic, L.; Trmcic, M.; Rodic, M.; Bihelovic, F.; Zlatar, M.;
Matovic, R.; Saicic, R. N. RSC Adv. 2015, 5, 99577.
(11) Terent’ev, A. O.; Borisov, D. A.; Yaremenko, I. A.; Chernyshev, V.
V.; Nikishin, G. I. J. Org. Chem. 2010, 75, 5065.
intervention of a C2 oxocarbenium ion meant that the anomer
ratio of the starting material input was irrelevant for the observed
product diastereomer ratio; diastereoconvergence was again
observed. The relative stereochemistry was confirmed by
obtaining crystal structures of compounds 15a, 15c, and 16
(see SI), and the remainder were assigned by analogy.30 The
stereochemistry of these compounds conform to the model of
nucleophilic attack “inside” the envelope of oxocarbenium ion
18, generating the staggered product as proposed by Woerpel.31
In summary, a simple protocol for the preparation of
spirocyclic endoperoxides has been established through the
aerobic oxidation of substituted Meldrum’s acid derivatives. The
strategy utilizes nearly every atom of the stoichiometric inputs, all
of which are cheap, readily available feedstock materials. Two
subsequent reductions provided highly substituted tetrahydro-
furans in diastereomerically pure form. The productive merger of
straightforward carbon skeletal assembly with downstream
complexity-building redox editing represents an attractive tactic
for the generation of polyfunctional structures.32
́
(12) Terent'ev, A. O.; Vil, V. A.; Bityukov, O. V.; Nikishin, G. I. Russ.
Chem. Bull. 2014, 63, 2461.
(13) Terent’ev, A. O.; Zdvizhkov, A. T.; Levitsky, D. O.; Fleury, F.;
Pototskiy, R. A.; Kulakova, A. N.; Nikishin, G. I. Tetrahedron 2015, 71,
8985.
(14) Yoshioka, M.; Sakuma, Y.; Saito, M. J. Org. Chem. 1999, 64, 9247.
(15) Haque, M. A.; Nishino, H. Synth. Commun. 2012, 42, 608.
(16) Rahman, T.; Haque, A.; Igarashi, H.; Nishino, H. Molecules 2011,
16, 9562.
(17) Steward, K. M.; Johnson, J. S. Org. Lett. 2011, 13, 2426.
(18) Cossy, J.; Belotti, D.; Bellosta, V.; Brocca, D. Tetrahedron Lett.
1994, 35, 6089.
(19) Vallejos, J.-C.; Capelle, N.; Arzoumanian, H. U.S. Patent
6,057,474, 2000.
(20) Li, D.; Yu, W. Adv. Synth. Catal. 2013, 355, 3708.
(21) Krabbe, S. W.; Do, D. T.; Johnson, J. S. Org. Lett. 2012, 14, 5932.
(22) Steward, K. M.; Gentry, E. C.; Johnson, J. S. J. Am. Chem. Soc.
2012, 134, 7329.
(23) Campbell, A. N.; Stahl, S. S. Acc. Chem. Res. 2012, 45, 851.
(24) Noyori, R.; Kitamura, M.; Ohkuma, T. Proc. Natl. Acad. Sci. U. S.
A. 2004, 101, 5356.
(25) Kaumanns, O.; Mayr, H. J. Org. Chem. 2008, 73, 2738.
(26) Duh, Y.-S.; Hui wu, X.; Kao, C.-S. Process Saf. Prog. 2008, 27, 89.
(27) Rubio, B. K.; Tenney, K.; Ang, K.-H.; Abdulla, M.; Arkin, M.;
McKerrow, J. H.; Crews, P. J. Nat. Prod. 2009, 72, 218.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b01225.
■
S
X-ray data of 15a (CIF), 15c (CIF), and 16 (CIF)
C
DOI: 10.1021/acs.orglett.7b01225
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(28) Kursanov, D. N.; Parnes, Z. N.; Loim, N. M. Synthesis 1974, 9,
633.
(29) Liu, T.; Wang, X.; Yin, D. RSC Adv. 2015, 5, 75794.
(30) CCDC 1485260 (15a), CCDC 1485259 (15c), and CCDC
1485261 (16) contain the supplementary crystallographic data for this
paper. This data can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/
cif.
(31) Larsen, C. H.; Ridgway, B. H.; Shaw, J. T.; Woerpel, K. A. J. Am.
Chem. Soc. 1999, 121, 12208.
(32) Ishihara, Y.; Baran, P. Synlett 2010, 12, 1733.
D
DOI: 10.1021/acs.orglett.7b01225
Org. Lett. XXXX, XXX, XXX−XXX