Ruthenium(0)-Catalyzed [4+2] Cycloaddition of Acetylenic Aldehydes with α-Ketols: Convergent Construction of Angucycline Ring Systems

Article abstract of DOI:10.1002/anie.201509646

Ruthenium(0) complexes modified by CyJohnPhos or RuPhos catalyze the successive C-C coupling of acetylenic aldehydes with α-ketols to form [4+2] cycloadducts as single diastereomers. This method enables convergent construction of type€...II polyketide ring systems of the angucycline class. Ringing with efficiency: Ruthenium(0) complexes modified by either CyJohnPhos or RuPhos catalyze the successive C-C coupling of acetylenic aldehydes with α-ketols to form [4+2] cycloadducts as single diastereomers. This method enables convergent construction of type€...II polyketide ring systems of the angucycline class.

Full text of DOI:10.1002/anie.201509646

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International Edition: DOI: 10.1002/anie.201509646
German Edition: DOI: 10.1002/ange.201509646
Cycloaddition
Ruthenium(0)-Catalyzed [4+2] Cycloaddition of Acetylenic
Aldehydes with a-Ketols: Convergent Construction of Angucycline
Ring Systems
Aakarsh Saxena, Felix Perez, and Michael J. Krische*
Abstract: Ruthenium(0) complexes modified by CyJohnPhos
À
or RuPhos catalyze the successive C C coupling of acetylenic
aldehydes with a-ketols to form [4+2] cycloadducts as single
diastereomers. This method enables convergent construction of
type II polyketide ring systems of the angucycline class.
À
I
n the course of developing C C bond-forming hydrogena-
tions and transfer hydrogenations,[1] we recently found that
zero-valent ruthenium complexes derived from [Ru3(CO)12]
À
and phosphine ligands catalyze a diverse array of C C
couplings between vicinally dioxygenated hydrocarbons (e.g.
diols, ketols, diones) and p-unsaturated reactants, including
dienes,[2a–c] acrylates,[2d] a-olefins,[2e] alkynes,[2f] and vinyl
acetates.[2g] As in related ruthenium(0)-catalyzed Pauson–
Khand-type reactions reported by Chatani and co-workers,[3]
these transformations proceed through catalytic mechanisms
=
=
involving C C/C O oxidative coupling to form oxaruthena-
cycles.[2c] However, rather than carbonylating, as in Pauson–
Khand-type reactions, the oxaruthenacycles undergo reduc-
tion by dehydrogenating alcohol reactants,[4] releasing prod-
uct, and regenerating the carbonyl partner required for
oxidative coupling. This pattern of reactivity served as the
basis for the design of novel [4+2] cycloadditions of 1,2-diols
with dienes,[5a] and a-ketols with 3,4-benzannulated 1,5-
diynes.[5b] Herein, we report that zero-valent ruthenium
catalysts promote the [4+2] cycloaddition of a-ketols with
ortho-acetylenic benzaldehydes, and demonstrate how this
transformation enables concise construction of ring systems
found in type II polyketides of the angucycline class.[6] This
cycloaddition is unique among metal-catalyzed reactions of
ortho-acetylenic benzaldehydes (Scheme 1).[7–17]
À
Scheme 1. Metal-catalyzed C C couplings of ortho-acetylenic benzalde-
hydes.
polyketides, we have begun to develop convergent methods
for their assembly that target ubiquitous substructures based
on redox-triggered cycloaddition. The studies presented here
are aimed at the rapid formation of angucycline ring systems
(Figure 1).[6]
Type II polyketide natural products, such as the tetra-
cyclines, daunorubicin, and doxorubicin, have found broad
use in human medicine.[18] Although total synthesis poten-
tially offers entry to otherwise inaccessible analogues, current
manufacturing routes rely on fermentation or semi-synthesis,
suggesting improved methods for de novo chemical synthesis
are necessary. The most common methods used for the
construction of type II polyketides are stoichiometric ben-
zannulations,[19] such as the Hauser reaction,[20] Diels–Alder
benzannulations,[21] the Dçtz reaction,[22] and aryne-mediated
benzannulation.[23] To further broaden access to type II
Figure 1. Selected type II polyketides of the angucycline class.
[*] Dr. A. Saxena, Dr. F. Perez, Prof. M. J. Krische
University of Texas at Austin, Department of Chemistry
105 E 24th St. A5300, Austin, TX 78712-1167 (USA)
E-mail: mkrische@mail.utexas.edu
Our initial experiments were guided by our earlier studies
on the ruthenium(0)-catalyzed [4+2] cycloadditions of a-
hydroxyketones with 3,4-benzannulated 1,5-diynes,[5b] which
involved exposure of the reactants to the ruthenium(0)
catalyst generated in situ from [Ru3(CO)12] (2 mol%) and
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201509646.
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CyJohnPhos (12 mol%; Figure 2), in m-
xylene/H2O at 60–858C. Gratifyingly, upon
application of these reaction conditions to
the cycloaddition of the ortho-acetylenic
arylaldehyde 1a with the para-fluorophenyl
a-ketol 2a, the targeted cycloadduct 3a
could be isolated as a single stereoisomer in
75% yield (Table 1). The syn-diol and (E)-
olefin stereochemistry were corroborated by single-crystal X-
ray diffraction analysis (see the Supporting Information).
Analysis of the crude reaction mixture by 19F NMR spectros-
copy revealed the presence of one major byproduct, which
was identified as the anti-diol (10:1 d.r.), as well as trace
quantities of the five-membered ring ketol.[24] Use of an
aqueous organic reaction solvent (m-xylene/H2O) was crucial
in terms of enforcing syn-diastereoselectivity and minimizing
formation of numerous byproducts. Additionally, precise
control of reaction temperature was required to preserve
(E)-alkene geometry and mitigate 1,2-ketol rearrange-
ment.[24]
Figure 2.
Ligands used in
this study.
Table 1: Ruthenium(0)-catalyzed [4+2] cycloaddition of ortho-acetylenic
benzaldehydes (1a–c) with a-ketols (2a–f).[a]
To establish the scope and limitation of this method,
acetylenic benzaldehydes (1a–c) were reacted with a diverse
set of a-ketols (2a–f), which incorporate both aryl (2a–e) and
alkyl (2 f) substituents (Table 1). In each case, slight variation
of reaction temperature was required to suppress formation
of undesired isomers. For 1a and 1b, the cycloadducts 3a–f
and 4a–f were formed in moderate to good yields and were
isolated in diastereomerically pure form. The ortho,ortho-
dimethoxy-substituted acetylenic benzaldehyde 1c proved to
be less reactive, requiring enhanced loadings of [Ru3(CO)12]
(3 mol%) and use of RuPhos (18 mol%) as ligand (Figure 2).
Under these reaction conditions, the cycloadducts 5a–f were
isolated as single diastereomers in moderate to good yields.
Among the a-ketols 2a–f, the ortho-substituted aryl ketol 2e
provided the lowest isolated yields of cycloadduct (3e, 4e,
5e). Analysis of the crude reaction mixtures by 1H NMR
spectroscopy indicated complete consumption of 2e in
reactions with acetylenic benzaldehydes 1a–c, however,
significant quantites of the undesired five-membered cyclo-
adduct were formed. Re-exposure of the six-membered
cycloadducts 3e, 4e, and 5e to the reaction conditions
resulted in conversion into the same distribution of five-
and six-membered ring products obtained from the initial
cycloaddition reactions, suggesting 3e, 4e, and 5e have
a lower barrier to 1,2-ketol rearrangement.[24]
A plausible catalytic mechanism, illustrated for the
coupling of 1a with 2, is as follows (Scheme 2): A mono-
nuclear ruthenium(0) complex[25] promotes alkyne–carbonyl
oxidative coupling of 1a with the a-ketoaldehyde dehydro-2
to form the oxaruthenacycle A.[2f] For the first turnover of the
catalytic cycle, the dicarbonyl partner required for oxidative
coupling (dehydro-2) may be formed through [Ru3(CO)12]-
catalyzed dehydrogenation of 2 with hydrogen transfer to
1a.[4] b-Hydride elimination converts A into the vinylruthe-
À
nium hydride B, which upon C H reductive elimination
delivers the tricarbonyl intermediate C, regenerating
À
ruthenium(0). The second C C bond formation may occur
by pinacol-type carbonyl–carbonyl oxidative coupling[3] to
deliver the dioxaruthenacycle D. Protonolytic cleavage of the
D, mediated by 2, forms the ruthenium alkoxide E. b-Hydride
elimination from V forms the alkoxyruthenium hydride F
[a] Yields are of material isolated by silica gel chromatography. See the
Supporting Information for further experimental details. [b] [Ru3(CO)12]
(3 mol%), RuPhos (18 mol%). TIPS=triisopropylsilyl.
À
with concomittant release of dehydro-2. Finally, O H reduc-
tive elimination delivers the product of cycloaddition, return-
ing ruthenium to its zero-valent form to close the catalytic
À
cycle. An alternate pathway for formation of the second C C
bond involves aldol reaction of a ruthenium enediolate
derived from C to form D. Remarkably, the secondary
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analysis of crude reaction mixtures, attempted isolation by
silica-gel chromatography triggered generation of the indi-
cated five-membered a-ketols.[24] Therefore, direct Friedel–
Crafts-type cyclization of the crude diones 7a, 7b, and 7c was
attempted. To our delight, exposure of 7a, 7b and 7c to
[27]
FeCl3
led to the formation of the desired cyclization
products 8a, 8b, and 8c, respectively, as single diastereomers.
The structural assignment of 8a and 8b was confirmed by
single-crystal X-ray diffraction analysis (see the Supporting
Information). Basic hydrolysis of the carbonate provided the
syn-triols 9a, 9b, and 9c, which upon IBX-mediated oxida-
tion[28] furnished the tetracyclic naphthoquinones 10a, 10b,
and 10c.
In summary, we report a novel [4+2] cycloaddition of
ortho-acetylenic benzaldehydes (1a–c) with a-ketols (2a–f)
À
by ruthenium(0)-catalyzed C C bond-forming transfer
hydrogenation. The dense functional group arrays embodied
by cycloadducts 3a–f, 4a–f, and 5a–f offer new possibilities
for the synthesis of type II polyketides, as demonstrated
through the conversion of 3 f, 4 f, and 5 f into tetracyclic
naphthoquinones 10a, 10b and 10c, respectively, bearing the
bridgehead diol substructure often found in angucycline
natural products.[6] More broadly, the transformations
reported in this account contribute to a growing body of
À
redox-neutral C C bond formations that emanate from the
merger of carbonyl addition and transfer hydrogenation.[1a]
Scheme 2. General catalytic mechanism for ruthenium(0)-catalyzed
[4+2] cycloaddition of ortho-acetylenic benzaldehydes (1a–c) with
a-ketols (2a–f).
benzylic alcohol of the
cycloadduct is not oxidized
under these reaction condi-
tions, suggesting ketol
dehydrogenation is more
rapid. Once the acetylenic
aldehyde, which serves as
hydrogen acceptor, is con-
sumed no further oxidation
occurs.
To illustrate how this
new [4+2] cycloaddition
methodology
broadens
access to type II poly-
ketides, the cycloadducts
3 f, 4 f, and 5 f were con-
verted into the respective
tetracyclic
naphthoqui-
Scheme 3. Conversion of the cycloadducts 3 f, 4 f, and 5 f into the tetracyclic naphthoquinones 10a, 10b, and
10c, respectively, bearing the bridgehead diol motif found in many angucycline natural products. DCM=di-
chloromethane.
nones 10a, 10b, and 10c
bearing the bridgehead diol
motif found in many angu-
cycline natural products
(Scheme 3).[6] The diols 3 f, 4 f, and 5 f were first treated Acknowledgments
with triphosgene to furnish the respective cyclic carbonates
Acknowledgements is made to the Robert A. Welch Foun-
dation (F-0038) and the NIH (RO1-GM093905) for partial
support of this research. Rusan Pharma Ltd. is acknowledged
6a, 6b, and 6c, which were then subjected to ruthenium-
catalyzed oxidative cleavage[26] to form the diones 7a, 7b, and
1
7c. Although 7a, 7b, and 7c could be observed by H NMR
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for partial financial support of Dr. Aakarsh Saxena. Dr. Felix
Perez is an NIH-IRACDA Postdoctoral Fellow (NIH
1K12GM102745). Kyle Bauernschmitt is acknowledged for
skillful technical assistance.
Keywords: cycloaddition · hydrogenation · natural products ·
polyketides · ruthenium
How to cite: Angew. Chem. Int. Ed. 2016, 55, 1493–1497
Angew. Chem. 2016, 128, 1515–1519
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Received: October 14, 2015
Revised: November 13, 2015
Published online: December 9, 2015
Angew. Chem. Int. Ed. 2016, 55, 1493 –1497
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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