Total syntheses of (±)-melicolones A and B

Article abstract of DOI:10.1021/acs.orglett.0c03454

The first total syntheses of (±)-melicolones A and B, which have a unique and densely functionalized framework derived from a rearranged prenylated acetophenone, were accomplished in 12.3% combined overall yield. The concise and divergent synthesis of these two natural products, which were isolated in racemic form, was achieved in a longest linear sequence requiring only 9 steps (11 total steps) and 8 isolated intermediates using commercially available starting materials. This approach, which might enable access to all tetracyclic melicolones, features the highly regioselective (16:1) and diastereoselective (15:1) dipolar cycloaddition of a carbonyl ylide generated by the unusual cyclization of a rhodium carbene with the carbonyl oxygen atom of an aliphatic aldehyde. This cycloaddition proceeds with dominant steric control to give a highly functionalized oxabicycloheptane core. Stereoselective enolate alkylation led to a prenylated intermediate that underwent an intramolecular aldol reaction to give the penultimate tricyclic intermediate. Tandem epoxidation of the pendant prenyl group followed by a regioselective, acid-catalyzed cyclization delivered (±)-melicolones A and B.

Full text of DOI:10.1021/acs.orglett.0c03454

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Total Syntheses of ( )-Melicolones A and B
Zhipeng Wang and Stephen F. Martin*
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ABSTRACT: The first total syntheses of ( )-melicolones A and B, which have a unique and densely functionalized framework
derived from a rearranged prenylated acetophenone, were accomplished in 12.3% combined overall yield. The concise and divergent
synthesis of these two natural products, which were isolated in racemic form, was achieved in a longest linear sequence requiring
only 9 steps (11 total steps) and 8 isolated intermediates using commercially available starting materials. This approach, which might
enable access to all tetracyclic melicolones, features the highly regioselective (16:1) and diastereoselective (15:1) dipolar
cycloaddition of a carbonyl ylide generated by the unusual cyclization of a rhodium carbene with the carbonyl oxygen atom of an
aliphatic aldehyde. This cycloaddition proceeds with dominant steric control to give a highly functionalized oxabicycloheptane core.
Stereoselective enolate alkylation led to a prenylated intermediate that underwent an intramolecular aldol reaction to give the
penultimate tricyclic intermediate. Tandem epoxidation of the pendant prenyl group followed by a regioselective, acid-catalyzed
cyclization delivered ( )-melicolones A and B.
elicolone A (1) and melicolone B (2) are epimeric
several having the same tetracyclic skeleton, as exemplified by
melicolones H (3), J (4), G (5), and I (6).3
M
natural products with an unprecedented 9-oxatricyclo
[3.2.1.13,8] nonane core that is derived from a prenylated
rearranged acetophenone. These unique compounds were
isolated in 2015 as racemates from the leaves of Melicope
ptelefolia, a deciduous shrub distributed in Southeast Asia, by
Kong and coworkers (Figure 1).1 Interest in the molecular
The remarkable structures of the diastereomeric melicolones
A and B (1 and 2) coupled with their promising biological
activity inspired us to develop a concise approach for their
synthesis that might be applied to the preparation of other
melicolones having a bridged oxabicycloheptane core. The
plan features the novel intermolecular dipolar cycloaddition of
the cyclic carbonyl ylide 10, which is generated in situ by the
rhodium(II)-catalyzed cyclization of the diazo compound 11,
with 9 to give the oxabicycloheptane 8 (Scheme 1).
Cycloadditions of such carbonyl ylides are well-known,4,5 but
these intermediates are generally formed by cyclization of a
metallocarbene with the carbonyl oxygen atom of a ketone,
ester, or amide; examples involving an aliphatic aldehyde are
rare.6 Another unusual aspect of the proposed cycloaddition of
9 and 10 is that the regiochemical outcome required to access
1 and 2 is opposite that expected based upon the usual
electronic effects; however, we reasoned that steric effects
would dominate this reaction to give 8 as the preferred
Figure 1. Structures of representative tetracyclic melicolones.
components found in many species of Melicope owes its origin
to a long history of their use in folk medicines.2 Indeed, both
enantiomers of 1 and 2 show potent cell protecting activities
against high glucose-induced oxidative stress in human vein
endothelial cells, suggesting they might be potential leads to
treat diabetic endothelial dysfunction. Since their discovery, a
number of other melicolones have been isolated, including
Received: October 15, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03454
© XXXX American Chemical Society
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respectively (Scheme 4). The structures of these compounds
were initially assigned based upon 2D NMR experiments, but
Scheme 1. Retrosynthetic Analysis of Melicolone A and B
Scheme 4. Rhodium(II)-Catalyzed Cycloaddition
the structure of 19 was unambiguously determined by X-ray
crystallography.9 After some experimentation, we discovered
that when 2 mol % Rh2(HNAc)4 was employed as the catalyst,
the cycloaddition was even more efficient and regioselective
(16:1) and furnished 19 in 61% isolated yield together with the
epimer 20 (4%) and the regioisomeric adduct 21 (4%). Our
original expectation that the regiochemical course of the
cycloaddition would be dominated by steric effects imposed by
the neopentyl center in the carbonyl ylide 10 was justified. The
high stereoselectivity of this reaction is rendered moot in the
subsequent enolate alkylation step, but it is also notable that
the cycloaddition proceeds with high exoselectivity (dr =
15:1), presumably because the endo-transition state is sterically
more hindered by the presence of the endo-methyl group of the
gem-dimethyl moiety. Although melicolones A and B occur in
nature as racemates, we briefly explored the use of chiral
rhodium catalysts to induce an enantioselective cycloadditio-
n,6a,b but the enantioselectivities using known catalysts were
low.
product. We further envisioned that 9 and 11 would be readily
accessible from the inexpensive starting materials 12 and 13,
respectively. Stereoselective prenylation of 8 then sets the stage
for an aldol cyclization to give 7, epoxidation and acid-
catalyzed cyclization of which will deliver a mixture of racemic
1 and 2.
Toward the pivotal carbonyl ylide cycloaddition, the
requisite starting materials 9 and 11 were prepared in a
straightforward fashion according to Schemes 2 and 3,
Scheme 2. Synthesis of Unsaturated Vinylogous Ester 9
Scheme 3. Synthesis of α-Diazo Ester 11
Inasmuch as the cycloadducts 19 and 20 were isolated in
pure form by chromatography, they were advanced separately
in the next step. Stereoselective prenylation from the sterically
more accessible exo-face of the enolate generated from 19
proceeded without detectable β-elimination10 of the bridging
oxygen atom to provide 22 in 65% yield (Scheme 5).
Scheme 5. Synthesis of Melicolones A and B
respectively. The known vinylogous carbonate 14, which
though commercially available, was readily prepared from
inexpensive methyl acetoacetate [CH(OMe)3, cat. H2SO4;
85%],7 was converted into 9 via the Weinreb amide 15 in 57%
overall yield (Scheme 2). Toward 11, the hydroxyl group of
hydroxypivalic acid (13) was first protected to give 16. The
acid moiety of 16 was then modified by activation with
carbonyldiimidazole (CDI) followed by a crossed-Claisen
reaction with the dianion of monomethyl malonate to provide
the keto ester 17 as an inconsequential mixture (3.5:1) of
keto−enol tautomers in 55% overall yield (Scheme 3).
Subjection of 17 to diazotransfer followed by direct oxidation
of the silyl protected alcohol 18 with iodoxybenzoic acid
(IBX)8 furnished 11 in 80% overall yield.
Prenylation of 20 under identical conditions furnished 22 in
the same yield, so the overall yield of 22 from 19 and 20 was
68%. Selective removal of the methyl ether group of 22 with
iodotrimethylsilane (TMS-I) produced an intermediate enol
that was not isolated but was subjected directly to base-
induced intramolecular aldol cyclization to give the penulti-
mate tricyclic intermediate 7 in 75% yield from 22.
The pivotal, rhodium(II)-catalyzed, carbonyl ylide cyclo-
addition was at hand. In an initial experiment, we were gratified
to discover that heating 9 and 11 in toluene in the presence of
2 mol % Rh2(OAc)4 was regioselective and gave a mixture of
three isomeric cycloadducts 19−21 in 37, 10, and 7% yields,
B
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Notes
Epoxidation of 7 with m-chloroperbenzoic acid (MCPBA)
followed by regioselective acid-catalyzed cyclization11 delivered
a mixture that was separated by reverse phase HPLC to give
( )-melicolone A (1) and ( )-melicolone B (2) in 44 and
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
1
41% yields, respectively. The H and 13C NMR spectra of
■
We are grateful to the Robert A. Welch Foundation (F-0652)
for funding. We also thank the UT Austin Mass Spectrometry
Facility for high-resolution mass spectral data, Dr. Vincent
Lynch and the UT Austin X-ray diffraction lab for crystallo-
graphic data, and the NIH (Grant 1 S10 OD021508-01) for
funding the Bruker AVANCE III 500 NMR spectrometer used
to characterize the synthetic intermediates.
synthetic 1 and 2 are consistent with those reported for the
corresponding natural products.1
In summary, we completed the first total syntheses of
( )-melicolone A (1) and ( )-melicolone B (2), which are
compact and densely functionalized natural products derived
from a rearranged prenylated acetophenone. This divergent
synthesis is remarkably concise and requires only 9 steps (11
total) and 8 isolated intermediates in the longest linear
sequence using commercially available starting materials.
Significantly, the strategy potentially represents a unified
approach to all melicolones containing a tetracyclic core.
The approach features an unusual and highly regioselective
(16:1) and stereoselective (15:1) dipolar cycloaddition of an
unsaturated vinylogous ester with a carbonyl ylide that is
generated by the cyclization of a rhodium carbene with the
carbonyl oxygen atom of an aliphatic aldehyde to create the
oxabicycloheptane core. A notable feature of this cycloaddition
is that the regiochemical and stereochemical outcomes are
dominated by steric effects rather than the more commonly
observed electronic ones. Stereoselective prenylation of each of
the epimeric cycloadducts having the correct regiochemistry
led to an intermediate that underwent facile intramolecular
aldol reaction to furnish the penultimate tricyclic intermediate.
Tandem epoxidation of the prenyl group followed by
regioselective acid-catalyzed opening delivered ( )-melico-
lones A and B in a combined overall yield of 12.3%.
REFERENCES
■
(1) Xu, J.; Zhao, H.; Wang, X.; Li, Z.; Luo, J.; Yang, M.; Yang, L.; Yu,
W.; Yao, H.; Luo, J.; Kong, L. ( )-Melicolone A and B, Rearranged
Prenylated Acetophenone Stereoisomers with an Unusual 9-
Oxatricyclo[3.2.1.13,8]nonane Core from the Leaves of Melicope
ptelefolia. Org. Lett. 2015, 17, 146−149.
(2) Johnson, A. J.; Kumar, R. A.; Rasheed, S. A.; Chandrika, S. P.;
Chandrasekhar, A.; Baby, S.; Subramoniam, A. Antipyretic, Analgesic,
Anti-inflammatory and Antioxidant Activities of Two Major
Chromenes from Melicope lunu-ankenda. J. Ethnopharmacol. 2010,
130, 267−271.
(3) Xu, J.; Han, C.; Xue, G.; Wang, X.; Luo, J.; Yang, M.; Luo, J.;
Kong, L. Novel Rearranged Acetophenone Derivatives Possessing
Diverse Architectures from the Leaves of Melicope ptelefolia.
Tetrahedron 2019, 75, 130784−130790.
(4) For reviews, see: (a) Padwa, A.; Weingarten, M. D. Cascade
Process of Metallo Carbenoids. Chem. Rev. 1996, 96, 223−269.
(b) Mehta, G.; Muthusamy, S. Tandem Cyclization-Cycloaddition
Reactions of Rhodium Generated Carbenoids from α-Diazo Carbonyl
Compounds. Tetrahedron 2002, 58, 9477−9504. (c) Padwa, A.
Domino Reactions of Rhodium(II) Carbenoids for Alkaloid Syn-
thesis. Chem. Soc. Rev. 2009, 38, 3072−3081. (d) Hodgson, D. M.;
Labande, A. H.; Muthusamy, S. In Organic Reactions, Vol. 80;
Denmark, S. D., Ed.; John Wiley & Sons: Hoboken, NJ, 2013; pp
133−496. (e) Ford, A.; Miel, H.; Ring, A.; Slattery, C. N.; Maguire, A.
R.; McKervey, M. A. Modern Organic Synthesis with α-Diazocarbonyl
Compounds. Chem. Rev. 2015, 115, 9981−10080.
(5) For related examples, see: (a) Kinder, F. R.; Bair, K. W. Total
Synthesis of ( )Illudin M. J. Org. Chem. 1994, 59, 6965−6967.
(b) Pirrung, M. C.; Kaliappan, K. P. Dipolar Cycloaddition of
Rhodium-Generated Carbonyl Ylides with p-Quinones. Org. Lett.
2000, 2, 353−355.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03454.
Experimental procedures, characterization data, spectral
comparison of synthetic and natural melicolones A and
1
B, and copies of H and 13C NMR spectra (PDF)
Accession Codes
(6) (a) Shimada, N.; Hanari, T.; Kurosaki, Y.; Takeda, K.; Anada,
M.; Nambu, H.; Shiro, M.; Hashimoto, S. Catalytic Asymmetric
Synthesis of the endo-6-Aryl-8-oxabicyclo[3.2.1]oct-3-en-2-one Natu-
ral Product from Ligusticum chuanxing via 1,3-Dipolar Cycloaddition
of a Formyl-Derived Carbonyl Ylide Using Rh2(S-TCPTTL)4. J. Org.
Chem. 2010, 75, 6039−6042. (b) Shimada, N.; Hanari, T.; Kurosaki,
Y.; Anada, M.; Nambu, H.; Hashimoto, S. Catalytic Asymmetric
Synthesis of Descurainin via 1,3-Dipolar Cycloaddition of a Carbonyl
Ylide Using Rh2(S-TCPTTL)4. Tetrahedron Lett. 2010, 51, 6572−
6575. (c) Svenda, J.; Hill, N.; Myers, A. G. A Multiply Convergent
Platform for the Synthesis of Trioxacarcins. Proc. Natl. Acad. Sci. U. S.
A. 2011, 108, 6709−6714.
CCDC 1992810 contains the supplementary crystallographic
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 Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
Stephen F. Martin − Department of Chemistry, The University
of Texas at Austin, Austin, Texas 78712, United States;
orcid.org/0000-0002-4639-0695; Email: sfmartin@
mail.utexas.edu
(7) Essig, S.; Bretzke, S.; Muller, R.; Menche, D. Full Stereochemical
̈
Determination of Ajudazols A and B by Bioinformatics Gene Cluster
Analysis and Total Synthesis of Ajudazol B by an Asymmetric
Ortholithiation Strategy. J. Am. Chem. Soc. 2012, 134, 19362−19365.
(8) Wu, Y.; Huang, J.; Shen, X.; Hu, Q.; Tang, C.; Li, L. Facile
Cleavage of Triethylsilyl (TES) Ether Using o-Iodoxybenzoic Acid
(IBX) without Affecting tert-Butyldimethylsilyl (TBS) Ethers. Org.
Lett. 2002, 4, 2141−2144.
(9) X-ray crystallographic data have been deposited with the
Cambridge Crystallographic Data Centre with the access number
1992810.
Author
Zhipeng Wang − Department of Chemistry, The University of
Texas at Austin, Austin, Texas 78712, United States
Complete contact information is available at:
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(10) For a related example, see: Padwa, A.; Sandanayaka, V. P.;
Curtis, E. A. Synthetic Studies toward Illudins and Ptaquilosin. A
Highly Convergent Approach via the Dipolar Cycloaddition of
Carbonyl Ylides. J. Am. Chem. Soc. 1994, 116, 2667−2668.
(11) Nicolaou, K. C.; Prasad, C. V. C.; Somers, P. K.; Hwang, C. K.
Activation of 6-Endo over 5-Exo Hydroxy Epoxide Openings.
Stereoselective and Ring Selective Synthesis of Tetrahydrofuran and
Tetrahydropyran Systems. J. Am. Chem. Soc. 1989, 111, 5330−5334.
D
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