Toward Naphthocyclinones: Doubly Connected Octaketide Dimers with a Bicyclo[3.2.1]octadienone Core by Thiolate-Mediated Cyclization

Article abstract of DOI:10.1002/anie.201503442

A viable method is reported for the synthesis of the bicyclo[3.2.1]octadienone scaffold in naturally occurring octaketide dimers. The procedure employs a reductive cyclization reaction mediated by an unusual ethanedithiol monosodium salt. Doubling up: A viable method for the construction of bicyclo[3.2.1]octadienone scaffolds has been developed, involving the reductive cyclization of dimeric naphthoquinone monoacetal mediated by the monosodium salt of 1,2-ethanedithiol. Bicyclo[3.2.1]octadienones may serve as key core units in the synthesis of biologically relevant naphthocyclinones.

Full text of DOI:10.1002/anie.201503442

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Angewandte
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International Edition: DOI: 10.1002/anie.201503442
German Edition: DOI: 10.1002/ange.201503442
Reductive Cyclization
Toward Naphthocyclinones: Doubly Connected Octaketide Dimers
with a Bicyclo[3.2.1]octadienone Core by Thiolate-Mediated
Cyclization**
Yoshio Ando, Subaru Hori, Takumi Fukazawa, Ken Ohmori,* and Keisuke Suzuki*
Abstract: A viable method is reported for the synthesis of the
bicyclo[3.2.1]octadienone scaffold in naturally occurring octa-
ketide dimers. The procedure employs a reductive cyclization
reaction mediated by an unusual ethanedithiol monosodium
salt.
Our working hypothesis to obtain doubly connected
octaketides is shown in Scheme 1. Given that one of the
starting naphthoquinones was reduced as in A, 1,4-addition of
D
imerization is one of natureꢀs strategies to increase
[
1]
molecular diversity and complexity. A good example is the
dimeric pyranonaphthoquinone antibiotics which are derived
[2]
from type II polyketide biosynthesis (Figure 1).
After
assembly of octaketide 1, cyclization forms a monomer,
[3]
specifically nanaomycin (2). Oxidative dimerization to form
[4]
a single connection (bond I) gives actinorhodin (3), whereas
dual connection (bonds I and II) leads to b-naphthocyclinone
[
5]
(
4). In view of the potential biological relevance and the
synthetic challenge of the unusual bicyclo[3.2.1]octadienone
[
6]
core in 4, we sought the chemical realization of such
dimerization reactions.
Scheme 1. Working hypothesis to obtain doubly connected
compounds.
A to B would give adduct C (forming bond I), which would
tautomerize into bishydroquinone D. Importantly, tauto-
mer E, possibly a minor species, provides an opportunity for
the second CÀC bond formation (bond II) by intramolecular
[
7]
aldol reaction to give aldol F and its tautomer G. This
hypothesis is a simplistic view, as complications may arise
from various equilibria by quinone–hydroquinone redox and
keto–enol tautomerism. A particular concern is the presum-
ably low concentration of tautomer E needed to achieve the
key aldolization.
To address this issue, we focused our attention on
bisacetal 6 as a model substrate in which bond I is already
formed. We attempted to prepare 6 by hydrogenating
bisenone 5, which was met with failure (see below). These
efforts, however, led us to discover a direct conversion of 5
into 7, containing the targeted skeleton, by an unusual
thiolate-mediated reductive cyclization [Eq. (1)], which will
be described herein.
Figure 1. One- and two-bond dimerization reactions.
[
*] Dr. Y. Ando, S. Hori, T. Fukazawa, Prof. Dr. K. Ohmori,
Prof. Dr. K. Suzuki
Department of Chemistry
Tokyo Institute of Technology
2
-12-1 O-okayama, Meguro, Tokyo 152-8551 (Japan)
E-mail: kohmori@chem.titech.ac.jp
ksuzuki@chem.titech.ac.jp
[
8]
Early attempts to saturate bisenone 5 to obtain 6 failed,
giving mostly bisphenol 8, resulting from the reductive
opening of acetals and aromatization on both sides
[
**] This work was supported by a Grant-in-Aid for Specially Promoted
Research from the JSPS (No. 23000006).
[
9]
(
Scheme 2). As an indirect access to 6, 1,4-addition of
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201503442.
thiolates to 5 was investigated, with the hope that dithiodi-
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Table 1: Ethanedithiol salts for the conversion of 5 into 7 (and 8).
Entry
thiolate
t [h]
yield [%]
7
8
1
2
2
3
–
56
EDT-2Na (10)
EDT-Na (11)
74
8
Figure 2. X-Ray structure of 12.
Scheme 2. Attempted preparation of model substrate. DMF=
dimethylformamide.
ketone 9 may allow for the key aldol reaction. Again the
[10]
attempts were fruitless, giving mostly 8. As this process
corresponds to a four-electron reduction (see the elemental
compositions of 8 relative to that of 5), the thiolates served as
[
11]
a reductant. This is not surprising in view of the highly
conjugated p system in 5.
During further attempts, the reagent 1,2-ethanedithiol
proved to be more successful. Use of its disodium salt EDT-
2
Na (10), generated from 1,2-ethanedithiol (6 equiv) and
NaH (15 equiv), invariably gave 8 (Table 1, entry 1). How-
ever, the reaction of excess 1,2-ethanedithiol (6 equiv) with
NaH (2 equiv) formed the reagent EDT-Na (11), whose
application in the reaction led to the formation of acetal 7
with the target bicyclo[3.2.1]octadiene structure in 74% yield
with bisnaphthol 8 (74% yield). Other monoanions of dithiols
led mostly to 8.
Further information to explain the effectiveness of 11 was
provided by the white precipitate formed in the reaction,
[
15]
which was identified as polyethylene disulfides 15.
This
[
12]
(
entry 2).
The structure of 7 was carefully verified by extensive 2D
suggested that EDT-Na (11) served as a two-electron
reductant by forming an SÀS bond to give 1,2-dithietane
[
13]
[16]
NMR spectroscopy and also by single-crystal X-ray dif-
(14), a putative species for the oxidation of ethanedithiol,
[17]
fraction analysis of ketone 12 (Figure 2), which was obtained
that undergoes facile conversion into oligomer 15 [Eq. (3)].
This dithiol–disulfide redox system is reminiscent of some
[13,14]
by acid hydrolysis of 7 (1m HCl, acetone, 92% yield).
[18]
Monitoring of the conversion of 5 into 7 by TLC suggested
the presence of an intermediate, which was identified as keto-
enone 13 by early quenching (10 min) [Eq. (2)]. 13 was shown
to be an active intermediate, as resubjecting it to the same
conditions led to the formation of product 7 in 82% yield.
For achieving this unusual reaction of 5 to form 7, EDT-
Na (11) turned out to be uniquely effective. Even its one-
carbon homologue, that is, the 1,3-propanedithiol mono-
sodium salt, gave only a small amount of 7 (17% yield) along
biological processes.
The question remained as to why EDT-Na (11) is so
efficient in the conversion of 5 into 7, in contrast to other
thiolates which convert 5 into 8. It should be noted that both
processes share a decrease of oxidation state of four electrons.
A known distinction between dithiols and monothiols is
[19]
their enhanced acidity and electron affinity,
which is
prominent with ethanedithiol (I; Figure 3). The higher acidity
of I is attributed to the stabilization of the monoanion II by
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a hydrogen bond. This stabilization also makes II less prone to
a single-electron release to give radical III.
tautomerization to F and aromatization by opening of the
cyclic acetal gives product 7.
These dithiol properties led us to assume that EDT-Na
(
11) is particularly effective because, as a less basic anion, it
The synthetic implications of this intriguing reaction were
subsequently addressed. We wondered whether we could use
the process to access unsymmetrical dimers with different
substitution patterns. To address this issue, model compound
serves as a good nucleophile for 1,4-addition rather than
electron transfer. Indeed, the model reaction with enone 16
and 11 gave 1,4-adducts 17 with varying lengths of oligomeric
disulfide chains [Eq. (4)], whereas the monosodium salt of
[
8]
23 was prepared (Scheme 4). Quinone monoacetal 19 and
1
,3-propanedithiol (not shown) gave mostly 18 (87%).
Figure 3. Ethanedithiol (I) and its monoanionic (II) and radical (III)
forms. II is stabilized by hydrogen bonding.
Scheme 3 shows a proposed mechanism consisting of two
stages. The first stage begins with the 1,4-addition of 11 to
enone 5, generating enolate A. Protonation gives thiolate B,
which is converted into dienolate C by expelling 1,2-
[
16,18a]
dithietane (14).
Protonation of dienolate C by ethane-
dithiol present in excess gives semireduced product 13 as an
intermediate. The second 1,4-addition of 11 to enone 13 gives
enolate D, which undergoes the key aldol reaction, giving
aldolate E with a bicyclo[3.2.1]octene skeleton. Finally,
Scheme 4. Preparation of keto-enone 23. a) [{RhCl(cod)} ], Et N, 1,4-
2
3
dioxane, H O, 91%; b) benzyl bromide, K CO , DMF; c) HF·pyridine,
2
2
3
pyridine; d) cerium(IV) ammonium nitrate, 1,4-dioxane, H O, 60%
2
(3 steps). cod=1,5-cyclooctadiene. TBS=tert-butyldimethylsilyl.
borane 20 were combined in
the presence of a rhodium cat-
alyst to give 1,4-adduct 21
[
20]
(91% yield).
Subsequent
benzylation, desilylation, and
oxidation gave keto-enone 23.
Note that the protecting groups
for the two rings are different
(methyl versus benzyl).
Exposure of keto-enone 23
to the key cyclization condi-
tions gave 24 as the single
product (Scheme 5), whose
structure was unambiguously
assigned by an extensive 2D
[13]
NMR spectroscopic study.
Although our focus was on
whether any scrambling to the
isomeric product happened or
not, the reaction gave only 24.
Acid hydrolysis of 24 and oxi-
dation gave quinone monoace-
tal 25, the structure of which
Scheme 3. Proposed reaction mechanism (isolated compounds are shown in gray squares).
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Chem. 1974, 1100 – 1125; c) B. Krone, A. Zeeck, Liebigs Ann.
Chem. 1983, 471 – 502; d) E. Egert, M. Noltemeyer, G. M.
Sheldrick, W. Saenger, H. Brand, A. Zeeck, Liebigs Ann.
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Chem. 1983, 510 – 518.
[
[
6] For the synthesis of bicyclo[3.2.1]octadienone skeletons, see:
a) W. R. Vaughan, M. V. Andersen, Jr., R. Q. Little, Jr., J. Am.
Chem. Soc. 1954, 76, 1748 – 1752; b) S. J. Cristol, F. P. Parungo,
D. E. Plorde, J. Am. Chem. Soc. 1965, 87, 2870 – 2879; c) H. Y.
Elnagar, K. H. Chow, A. T. Johnson, R. Somanathan, P. Nunez,
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841 – 5848.
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[
[
8] For the substrate preparation, see the Supporting Information.
9] Pd/C, Rh/C, and Wilkinsonꢀs catalysts were studied.
Scheme 5. Reductive cyclization of 23 and X-ray structure of 25.
a) Aqueous HCl (1m), acetone, 80%; b) PhI(OCOCF ) , CH CN, 89%.
3
2
3
[
[
10] Thiolates derived from PhSH, EtSH, and C H SH were
12 25
examined.
11] For thiolates as reducing agents, see: a) M. J. Gibian, D. V.
Winkelman, Tetrahedron Lett. 1969, 10, 3901 – 3904; b) H.
Bayley, D. N. Standring, J. R. Knowles, Tetrahedron Lett. 1978,
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1981, 103, 182 – 184.
was confirmed by single-crystal X-ray diffraction analysis
[
14]
(
Scheme 5).
In conclusion, we have discovered a method for con-
structing the bicyclo[3.2.1]octadienone structure which serves
as the core unit in the naphthocyclinone class of dimeric
natural products. Further studies are in progress.
[
12] Other base/solvent combinations were demonstrated to be
ineffective: KH, CaH2, 1,8-diazabicyclo[5.4.0]undec-7-ene
(
DBU), nBuLi, and iPrMgCl; THF, CH Cl , toluene, N-
2 2
methyl-2-pyrrolidone (NMP), N,N-dimethylacetamide (DMA),
,3-dimethyltetrahydropyrimidin-2(1H)-one (DMPU), and
dimethylsulfoxide (DMSO).
1
Experimental Section
Synthesis of acetal 7: To a solution of 1,2-ethanedithiol (38 mL) in
DMF (750 mL) was added NaH (63% dispersion in oil, 6 mg) at 08C.
After stirring for 15 min at RT, the mixture was cooled to 08C, to
which was added bis-enone 5 (29.5 mg). After stirring for 3 h at RT,
the reaction was quenched using phosphate buffer (pH 7, 08C). The
reaction mixture was extracted using EtOAc (” 3) and purified twice
by preparative TLC (using a mixture of toluene:acetone, 2/1 v/v) to
give 7 (22.0 mg, 74%) as a colorless oil and 8 (2.3 mg, 8%) as a white
solid.
[13] See the Supporting Information.
[14] CCDC-873993 (12) and 1051963 (25) contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
À1
[15] In the Raman spectrum, bands at 505 cm (SÀS bond) and
À1
726 cm (CÀS bond) were detected, and in the EI mass
spectrum fragmentation signals were found from the mono-,
di-, tri-, and tetramers. For polyethylene disulfide, see: a) J. G.
Affleck, G. Dougherty, J. Org. Chem. 1950, 15, 865 – 868; b) N.
Kobayashi, A. Osawa, T. Fujisawa, J. Polym. Sci. B 1973, 11,
Keywords: cyclization · dimerization · dithiol reagents ·
quinones · synthetic methods
2
25 – 228; c) E. I. Stout, B. S. Shasha, W. M. Doane, J. Org.
Chem. 1974, 39, 562 – 563.
[
16] For 1,2-dithietane, see: a) M. Platen, E. Steckhan, Chem. Ber.
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Published online: June 26, 2015
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