Toward Chromanes by de Novo Construction of the Benzene Ring

Article abstract of DOI:10.1021/acs.orglett.9b03209

The work describes three principal Diels-Alder cycloaddition approaches toward chromanes that are designed for the de novo construction of the benzene ring. This study specifically focuses on the potential exploitation in the total synthesis of chromane-bearing natural products such as cebulactam A.

Full text of DOI:10.1021/acs.orglett.9b03209

Letter
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Toward Chromanes by de Novo Construction of the Benzene Ring
†,§
‡
†
,†
Egor Geist,†,§ Helge Berneaud-Kotz, Tomas Baikstis, Gerald Drager, and Andreas Kirschning*
̈
̈
†
̈
Institute of Organic Chemistry and Center of Biomolecular Drug Research (BMWZ) at Leibniz Universitat Hannover,
Schneiderberg 1B, 30167 Hannover, Germany
‡Sygnature Discovery, Biocity, Pennyfoot Street, Nottingham NG11GR, United Kingdom
S
* Supporting Information
ABSTRACT: The work describes three principal Diels−
Alder cycloaddition approaches toward chromanes that are
designed for the de novo construction of the benzene ring.
This study specifically focuses on the potential exploitation in
the total synthesis of chromane-bearing natural products such
as cebulactam A.
hromanes and derivates, such as coumarins,1 chromenes,
or chromane spiroketals,2 are building blocks that are
widely found in bioactive natural products. They constitute the
core structures of tocopherols, flavonoids, cannabinoids, as
well as many bioactive unnatural products, making them
indispensable for medicinal chemistry (structures 1−7, Figure
1).
Scheme 1. Concepts A−C for the de Novo Preparation of
a
C
the Aromatic Moiety in Chromanes
The common synthetic approach toward these kind of
structural motifs includes an aromatic starting material, which
a
EWG, electron-withdrawing group.
is functionalized and cyclized to the chromane backbone,
whereas strategies that rely on the de novo syntheses of the
aromatic core are, except for the Bergman cyclization3 and the
tetra/hexa-dehydro Diels−Alder reaction, rare.4 When consid-
ering Diels−Alder approaches, one can suggest three viable
retrosynthetic disconnections for the benzene moiety (Scheme
1). Strategy A positions the oxygen functionality at the
terminus of the diene system 8. Here an electron-deficient
acetylene derivative or synthetic equivalent 9 can be chosen as
a dienophile. Strategy B relies on diene 11, in which the
Figure 1. Structures of selected classes of chromane containing
natural products 1−7.
Received: September 10, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03209
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Preparation of Tetrahydropyran 20 and
Acetonide Derivative 21 for Determining the Relative
Stereochemistry by NMR Spectroscopy
Scheme 4. Diels−Alder Strategy B
a
a
DIPEA, diisopropylethyl amine; TBAF, tetra-n-butylammonium
fluoride; TBS, tert-butyldimethylsilyl; CSA, camphorsulfonic acid.
a
Scheme 3. Diels−Alder Strategy A
a
DTBBP, 4,4′-di-tert-butylbiphenyl; MOM, methoxymethyl; DDQ,
2,3-dichloro-5,6-dicyano-1,4-benzoquinone.
tetrade in diol 19. O-Benzyl protection in ketone 17 is crucial
for achieving the desired 1,4-syn stereorelationship with very
good diastereomeric excess, as judged after the derivatization
of diol 19 and the formation of acetonide 21.7
McDonald and coworkers reported on the photolysis of
W(CO)6 in the presence of alkynyl alcohols, which induces a
cycloisomerization to endocyclic enol ethers.8 In the present
case, we exploited this method but had to silylate the
propargylic alcohol first to achieve cyclization. Excellent
regioselectivity was achieved by the slow addition of TBSOTf
at 0 °C. Gratifyingly, the cycloisomerization yielded enol ether
20 in very good yield.
For realizing strategy A, a vinyl group was installed in the β-
position of the enol ether group (Scheme 3). This was
achieved by bromination through an addition/elimination
mechanism, followed by a Stille cross-coupling reaction. To
achieve acceptable yields, the presence of the ligand AsPh3 was
essential.9 The resulting diene was subjected to Diels−Alder
cycloaddition conditions using β-sulfinylnitro ethylene 23
(equals 9 in Scheme 1), a nitroacetylene equivalent reported
by Ono et al.10 After the cycloaddition and formation of
cycloadduct 24, the elimination of sulfenic acid occurs to
afford 1-nitro-1,4-cyclohexadiene 25. It was planned to form
the bicyclic coumarin ring system 10 upon oxidative
aromatization, but rather we found nitrobenzene 26 upon
purification. Obviously, intermediate 25 undergoes a vinyl-
ogous elimination that ring-opens the pyran ring.11 Never-
theless, this approach is principally feasible for the de novo
construction of substituted benzene rings in natural product
synthesis.
a
dba, dibenzylideneacetone.
oxygen substituent is positioned at C2, whereas alkyne 12
serves as dienophile.
In contrast, strategy C utilizes enol ether 14 as dienophile in
the reaction with an electron-deficient δ-lacton 15. In this case,
cycloaddition followed by a retro-Diels−Alder reaction yields
the cyclohexane ring.
All strategies initially yield functionalized 2,4-cyclohexa-
dienes that need to be oxidized to form the aromatic ring
system, as depicted for benzenes 10, 13, and 16, respectively.
In this work, we investigate all three options for the de novo
synthesis of the chromane backbone with the ultimate goal of
synthetically accessing ansamycin antibiotic cebulactam A1
(6),5 a macromlactam antibiotic that belongs to the class of
polyketide-derived ansamycins.6
To evaluate the feasibility of all three strategies for the
synthesis of cebulactam A1 (6), we chose the complex, highly
substituted dihydropyran 20 to serve as general precursor. Its
synthesis commenced by transforming ethyl (S)-lactate into
ketone 17 via the corresponding pyrrolidine amide (Scheme
2). Next, the titanium-mediated aldol reaction with aldehyde
18 yielded the aldol product with 1,4-syn stereochemistry. This
underwent a 1,3-anti reduction and established the stereo-
In contrast, the second strategy B cannot yield a
dihydrobenzene that would be prone to aromatization through
Grob-type elimination. Consequently, we prepared diene 28
from enol ether 27, which itself was obtained from the central
B
DOI: 10.1021/acs.orglett.9b03209
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
benzene in the presence of a catalytic amount of hydroquinone
to yield the desired dehydrobenzene 30a along with the diene
isomer 30b. Gratifyingly, both dehydrobenzenes 30 could be
oxidized to the desired benzene 31 using DDQ as the oxidant.
The control of conditions is essential because the use of an
excess of DDQ can lead to the cleavage of the silyl ether, and
this is followed by the oxidation to the corresponding
acetophenone derivative.
Scheme 5. Diels−Alder Strategy C
This cycloaddition protocol did not provide preparatively
acceptable yields, which also included the use of other
dienophiles such as methyl propiolate 29b13 and trifluoro-
but-3-yn-2-one 29c.14 Therefore, we searched for Lewis acids
to promote the cycloaddition.15 Among AlCl3, Et2AlCl, AlMe3,
BF3OEt2, LiClO4, MgBr2, SnCl4, ScOTf3, TiCl4, Ti(OiPr)3Cl,
Ti(OiPr)4, and ZnCl2, only the use of Et2AlCl provided the
cycloaddition product 30 in low yield, especially when the TBS
protecting group in enolether 28 was exchanged for the
triisopropylsilyl (TIPS) group. (See the SI.) Finally, the
cycloaddition under high-pressure conditions was investi-
gated.16 Indeed, pressurizing a solution of alkyne 29a and
diene 28 at 14 kbar over a period of 15 h using a hydraulic
press furnished the desired dehydrobenzenes 30. This time, the
formation of the byproduct diacetylchromane 33 could
unequivocally be identified. This product is derived from the
tricyclic product 32 that itself arises from a second Diels−
Alder reaction of the isomerized dehydrobenzene 30b with
acetylene 29a. Under the given conditions, the extrusion of
ethylene must have taken place, which is accompanied by
rearomatization by means of a retro Diels−Alder reaction. The
formation of these byproducts could not be suppressed when
varying the pressure and reaction time. In fact, when instead of
a TBS group the TIPS-protecting group was installed in
chromane 31, intermediate 32 (R = TIPS) could be isolated
and fully characterized. (See the SI.) Because of these side
reactions, the combined yields of cycloaddition and oxidation
were preparatively not satisfactory.
Consequently, we pursued strategy C utilizing dehydropyran
of type 14 as dienophile and methyl 2-oxo-2H-pyran-5-
carboxylate 15 as diene to construct a highly substituted
chromane core by utilizing a cycloaddition/cycloreversion
sequence followed by oxidation (Scheme 5).
Scheme 6. Transformation of Diels−Alder Adduct 38 to
Hydroquinone Derivative 40
Thus the simplest dihydropyran 34 was converted into the
tricyclic exo- and endo-cyclization products 35a,b under high-
pressure conditions. After substantial optimization, we found
that it is only possible to initiate cycloaddition under high-
pressure conditions at room temperature over an extended
time. In this first case, both crystalline cycloaddition products
35a,b were separated and structurally characterized by X-ray
analysis. Next, both diastereomers underwent a retro Diels−
Alder reaction with the extrusion of carbon dioxide under
thermal conditions, which provided dehydrobenzene 36, which
was dehydrogenated to yield chromane derivative 37 using
DDQ as an oxidant.17 This three-step protocol also works for
the complex dihydropyran 27 and provided chromane
derivative 38, which can principally serve as a precursor for
the synthesis of cebulactam A1 (6).
This would require the transformation of the methyl
benzoate group into the corresponding hydroquinone
derivative. This was achieved after the reduction/oxidation of
ester 38 to the corresponding benzaldehyde 39 (Scheme 6).
Dakin oxidation with 3-chloroperbenzoic acid smoothly
yielded formiate 40 in quantitative yield.18
precursor 20 (Scheme 4). The exchange of the benzyl by the
MOM group was required to obtain clean lithiation in the
following. It has to be noted that DIPEA is the solvent of
choice for efficient MOM protection. Next, the vinyl group was
introduced to yield diene 28, which was achieved by α-
lithiation of the enol ether, followed by iodination that paved
the way for the Stille cross-coupling reaction with vinyl
stannane. The reversal of the coupling steps (vinyl iodide with
an 1-stannylated enol ether) provided diene 28 in only low
yield. With the cycloaddition precursor 28 in hand, we engaged
in the Diels−Alder reaction. On the basis of the work of Wada
and coworkers,12 we first envisaged a thermal protocol.
Accordingly, but-3-yn-2-one 29a was heated with diene 28 in
C
DOI: 10.1021/acs.orglett.9b03209
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(11) Weyerstahl, P.; Marschall, H. Heteroatom Manipulation. In
Comprehensive Organic Synthesis: Selectivity, Strategy, and Efficiency in
Modern Organic Chemistry; Trost, B. M., Fleming, I., Eds.; Pergamon
Press: 1991; Vol. 6, pp 1044−1065.
Overall, we provided three unconventional approaches
embedded in a natural-product-like environment that disclose
new synthetic avenues toward substituted chromane back-
bones. In particular, the last strategy has the potential to be
broadly applied in natural product synthesis, especially of the
chromanes listed in Figure 1. It will be a versatile addition to
known de novo strategies.3,4,19
(12) Wada, E.; Kanemasa, S.; Tsuge, O. Bull. Chem. Soc. Jpn. 1989,
62, 1198−1204.
(13) (a) Alvarez-Manzaneda, E. J.; Chahboun, R.; Cabrera, E.;
Alvarez, E.; Haidour, A.; Ramos, J. M.; Alvarez-Manzaneda, M.;
Hmamouchi, M.; Bouanou, H. J. Org. Chem. 2007, 72, 3332−3339.
ASSOCIATED CONTENT
* Supporting Information
́
(b) Alvarez-Manzaneda, E.; Chahboun, R.; Alvarez, E.; Fernandez, A.;
■
Alvarez-Manzaneda, R.; Haidour, A.; Ramos, M. J.; Akhaouzan, A.
Chem. Commun. 2012, 48, 606−608.
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03209.
(14) (a) Koldobskii, A. B.; Solodova, E. V.; Godovikov, I. A.;
Kalinin, V. N. Russ. Chem. Bull. 2008, 57, 1568−1570. (b) Tsvetkov,
N. P.; Koldobskii, A. B.; Korznikova, I. V.; Peregudov, A. S.; Kalinin,
V. N. Dokl. Chem. 2006, 408, 87−89.
Detailed experimental procedures and spectral data
(PDF)
(15) Dias, L. C. J. Braz. Chem. Soc. 1997, 8, 289−332.
(16) Flessner, T.; Ludwig, V.; Siebeneicher, H.; Winterfeldt, E.
Synthesis 2002, 16, 1373−1378.
(17) Although oxidative aromatization proceeded quantitatively, as
judged chromatographically including TLC; isolation turned out to
lead to the loss of material.
(18) Yaremenko, I. A.; Vil’, V. A.; Demchuk, D. V.; Terent’ev, A. O.
Beilstein J. Org. Chem. 2016, 12, 1647−1748.
(19) Alternative biomimetic de novo strategies of polyketide-based
benzene units were developed by the group of Barrett: (a) Cookson,
Accession Codes
CCDC 1948955 and 1949004 contain 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
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
̈
R.; Poverlein, C.; Lachs, J.; Barrett, A. G. M. Eur. J. Org. Chem. 2014,
2014, 4523−4535. (b) Barrett, T. N.; Patel, B. H.; Barrett, A. G. M.
AUTHOR INFORMATION
Corresponding Author
■
Tetrahedron 2014, 70, 6894−6901.
*E-mail: andreas.kirschning@oci.uni-hannover.de.
ORCID
Andreas Kirschning: 0000-0001-5431-6930
Author Contributions
§E.G. and H.B.-K. contributed equally to the work presented.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
̈
̈
We thank Dr. Jorg Fohrer (Leibniz Universitat Hannover,
Hannover, Germany) for excellent support in the structural
analysis of NMR spectroscopic data.
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DOI: 10.1021/acs.orglett.9b03209
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