Enantioselective Ruthenium-Catalyzed Benzocyclobutenone-Ketol Cycloaddition: Merging C-C Bond Activation and Transfer Hydrogenative Coupling for Type II Polyketide Construction

Article abstract of DOI:10.1021/jacs.8b05724

The first enantioselective intermolecular metal-catalyzed cycloadditions of benzocyclobutenones via C-C bond oxidative addition are described. In the presence of a ruthenium(0) complex modified by (R)-DM-SEGPHOS, tetralone-derived ketols and benzocyclobutenones combine to form cycloadducts with complete regio- and diastereoselectivity and high enantioselectivity. Using this method, the "bay region" substructure of the angucycline natural product arenimycin was prepared.

Full text of DOI:10.1021/jacs.8b05724

Communication
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Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Enantioselective Ruthenium-Catalyzed Benzocyclobutenone−Ketol
Cycloaddition: Merging C−C Bond Activation and Transfer
Hydrogenative Coupling for Type II Polyketide Construction
Brett R. Ambler,# Ben W. H. Turnbull,# Sankar Rao Suravarapu,# Maulen M. Uteuliyev,
Nancy O. Huynh, and Michael J. Krische*
University of Texas at Austin, Department of Chemistry, Austin, Texas 78712 United States
S
* Supporting Information
Table 1. Selected Optimization Experiments in the
ABSTRACT: The first enantioselective intermolecular
metal-catalyzed cycloadditions of benzocyclobutenones via
C−C bond oxidative addition are described. In the presence
Enantioselective Intermolecular Ruthenium-Catalyzed
a
Cycloaddition of Benzocyclobutenones
of a ruthenium(0) complex modified by (R)-DM-SEGPHOS,
tetralone-derived ketols and benzocyclobutenones combine
to form cycloadducts with complete regio- and diastereo-
selectivity and high enantioselectivity. Using this method,
the “bay region” substructure of the angucycline natural
product arenimycin was prepared.
ollowing the pioneering work by Liebeskind,1,2 Jun,3 and
4
FMurakami, the insertion of π-bonds into metallacycles
obtained through C−C bond oxidative addition has matured
into an active area of research.5 Despite substantial progress in
this field, several key challenges persist. The use of directing
groups is often required to overcome the kinetic and thermo-
dynamic barriers posed by the activation of relatively strong
a
and stable C−C bonds. Many C−C bond activation initiated
C−C couplings are restricted to intramolecular processes.
Finally, beyond reactions of donor−acceptor cyclopropanes,6,7
enantioselective intermolecular metal-catalyzed C−C bond activa-
tion initiated C−C couplings are exceptionally uncommon.8
In connection with studies of transfer hydrogenative C−C
bond formation,9 we recently developed a novel class of
ruthenium(0)-catalyzed cycloadditions of vicinal diols, ketols
or diones.9d,10 These processes operate through a common
mechanistic motif wherein oxidative formation of ruthenium-
(II) metallacycles, which is accompanied or triggered by dione
addition, is followed by diol- or ketol-mediated transfer hydro-
genolysis of the ruthenacycle to release product and regener-
ate the reactive dione (Figure 1).9d Recently, we found that
Yields are of material isolated by silica gel chromatography.
Enantioselectivity values were determined by HPLC analysis on a
b
chiral stationary phase. (R)-SEGPHOS (Ar = phenyl). Reaction was
conducted from the diol oxidation level, 1a−1c (200 mol%).
c
1c (130 mol%), (R)-DM-SEGPHOS (Ar = 3,5-xylyl). See the
Supporting Information for further experimental details.
ruthenacycles obtained via C−C bond oxidative addition to
benzocyclobutenones are catalytically competent in trans-
formations of this type, providing a kinetic pathway for the
insertion of adjacent carbon atoms of vicinal diols, ketols or
diones into C−C σ-bonds.10i On the basis of this finding,
we now report the first examples of enantioselective inter-
molecular metal-catalyzed cycloadditions of benzocyclobut-
enones.11−14
In an initial set of experiments (Table 1), a series of benzo-
cyclobutenone derivatives 1a−1d were exposed to equimolar
quantities of tetralone-derived ketols 2a−2c (or diols) in the pre-
sence of the mononuclear ruthenium(0) catalyst15 derived from
Ru3(CO)12 and (R)-SEGPHOS in m-xylene (1 M) at 150 °C.
The reaction of unsubstituted benzocyclobutenone 1a with
unsubstituted diol 2a led to the formation of cycloadduct 3a
with complete regio- and diastereoselectivity but in nearly
Received: May 31, 2018
Figure 1. General catalytic mechanism for ruthenium(0)-catalyzed
cycloaddition of diols, ketols or diones.
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.8b05724
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Communication
Table 2. Enantioselective Intermolecular Ruthenium(0)-
Scheme 1. Arenimycins A−D and Collinone, Antibacterial
Angucyclines That Incorporate a Bridgehead Diol Motif,
and Reaction of Benzocyclobutenone 1c with Ketol 2g To
Catalyzed Cycloaddition of Benzocyclobutenones 1c, 1e−1l
a
with Ketols 2c−2f To Form Cycloadducts 3h−3s
a
Form Cycloadduct 3t
a
For structurally related angucycline natural products, SF22446A1−A3
and SF22446B1−B3, see ref 19. Reaction was performed on
0.20 mmol scale. Yield of material isolated by silica gel chromatog-
raphy. Enantioselectivities were determined by chiral stationary phase
HPLC analysis. See Supporting Information for further experimental
details.
a
All reactions were performed on a 0.20 mmol scale. Yield of
material isolated by silica gel chromatography. Enantioselectivities
were determined by chiral stationary phase HPLC analysis. See the
Retaining key structural features required to enforce high levels
of asymmetric induction, an otherwise diverse set of benzo-
cyclobutenones 1c, 1e−1l, were reacted with ketol 2c to
furnish cycloadducts 3h−3p. In each case, complete regio- and
diastereoselectivity were accompanied by excellent levels of
enantiomeric enrichment. The formation of 3o and 3p
illustrates tolerance of activated aryl chlorides. Variation of
the ketol partner also was explored. As demonstrated by the
formation of cycloadducts 3q−3s, electron-releasing substitu-
ents that reside in a para-relationship with respect to the
ketone improve enantioselectivity, precluding the need for an
ortho-benzyloxy-group. For example, in the formation of cyclo-
adduct 3r, a 99:1 enantiomeric ratio is observed. The forma-
tion of 3r also demonstrates compatibility with amine func-
tional groups.
b
Supporting Information for further experimental details. X-ray
c
structure obtained after removal of silyl ether (3h′). Reaction
time = 36 h.
racemic form (Table 1, entry 1). However, using the
corresponding ortho-methoxy-substituted benzocyclobutenone,
1b, cycloadduct 3b was formed with significant levels of
enantiomeric enrichment (Table 1, entry 2). On the basis of
this result, an effort was made to define substituents that would
both enforce optimal levels of enantiomeric enrichment and
facilitate entry to naturally occurring type II polyketides of the
angucycline class (vide infra). Toward this end, incorporation
of a triisopropylsilyl (TIPS) ether at C2 of the benzocyclo-
butenone, as in 1c, and for the ketol partner, a benzyloxy
substituent at C8, as in 2c, conspired to improve the degree of
asymmetric induction. Thus, the reaction of benzocyclobut-
enone 1c and ketol 2c delivered cycloadduct 3h with complete
regio- and diastereoselectivity as a 94:6 ratio of enantiomers
(Table 1, entry 8). Finally, using (R)-DM-SEGPHOS as ligand
and a slight excess of benzocyclobutenone 1c, cycloadduct 3h
was generated in 96% yield as a single regio- and diastereomer
as a 97:3 ratio of enantiomers (Table 1, entry 9).
̀
Underscoring the utility of this method vis-a-vis construc-
tion of type II polyketides, in particular, the angucycline anti-
biotics arenimycins A−D, collinone and SF22446A1−A3/
SF22446B1−B3,16−19 benzocyclobutenone 1c was exposed to
ketol 2g under standard conditions for ruthenium-catalyzed
cycloaddition (Scheme 1). Cycloadduct 3t was formed in good
yield and incorporates the highly congested “bay region” motif
found in arenimycin. To further demonstrate relevance to type
II polyketide construction, cycloadduct 3h was subjected to
silyl-deprotection followed by oxidation of the resulting alcohol
to form dione 4h (eq 1):
The scope of the enantioselective ruthenium-catalyzed benzo-
cyclobutenone-ketol cycloaddition was evaluated (Table 2).
B
DOI: 10.1021/jacs.8b05724
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Communication
ruthenaindanone formation accounts for structural features of the
benzocyclobutenone that are required to enforce high levels
of enantioselectivity, specifically, nonbonded interactions
between the methoxy and triisopropylsiloxy groups of the
α-oxo-ortho-quinodimethane with the xylyl moieties of
DM-SEGPHOS.
In summary, we report the first enantioselective intermo-
lecular metal-catalyzed cycloadditions of benzocyclobutenones
via C−C bond oxidative addition. Using a mononuclear15
ruthenium(0) complex derived from Ru3(CO)12 and (R)-DM-
SEGPHOS, tetralone-derived ketols and benzocyclobutenones
react to form cycloadducts with complete regio- and diastereo-
selectivity and high enantioselectivity. Whereas the majority of
methods for convergent type II polyketide construction require
use of stoichiometric carbanions under cryogenic con-
ditions (e.g., the Hauser-Kraus annulation,23,24 aryne-mediated
cycloadditions),25 the present method assembles type II poly-
ketide motifs in the absence of stoichiometric byproducts
under noncryogenic conditions. In an initial synthetic applica-
tion, this method was used to prepare the congested “bay region”
substructure characteristic of the angucycline antibiotics areni-
mycin, collinone and SF22446A1−A3/SF22446B1−B3.16−19
Future studies are aimed at defining ketol partners for the
synthesis of linear tetracycline antibiotics.26
Additionally, cycloadduct 3o was subjected to an SNAr reac-
tion to form compound 4o, which incorporates a dimethyl-
amino motif (eq 2). Dimethylamino groups frequently occur in
type II polyketide antibiotics (e.g., the tetracyclines), and as
recently demonstrated by Hergenrother, introduction of unhin-
dered amines endows certain rigid Gram-(+) only antibacterials
with Gram-(−) activity by conferring membrane permeability.20
Finally, the ability to achieve high levels of enantioselectivity
in cycloadditions of chiral racemic benzocyclobutenones 1c,
1e−1l, has implications regarding the nature of the C−C bond
oxidative addition event. High levels of enantiomeric enrich-
ment persist at equimolar loadings of benzocyclobutenone and
ketol (Table 1, entry 8) and do not depend on stoichiometry,
which suggests kinetic resolution of benzocyclobutenones 1c,
1e−1l, is not operative. Rather, these data corroborate a
catalytic mechanism wherein stereoablative cycloreversion to
form a discrete α-oxo-ortho-quinodimethane or “ortho-quinoid
ketene methide”21 is followed by enantiodetermining C−C
bond oxidative addition to form a ruthenaindanone com-
plex (Figure 2).22 The indicated stereochemical model for
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.8b05724.
Experimental procedures and spectral data. HPLC traces
of racemic and enantiomerically enriched products.
Crystallographic data for 3h′ (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*mkrische@mail.utexas.edu
ORCID
Michael J. Krische: 0000-0001-8418-9709
Author Contributions
#B.R.A., B.W.H.T., and S.R.S. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The Robert A. Welch Foundation (F-0038), the NIH-NIGMS
(RO1-GM093905). Dr. Ping-Xin Zhou is acknowledged for
technical assistance. The Swiss National Science Foundation
(SNSF) is acknowledged for early postdoctoral mobility
fellowship (SRS, P2BEP2_172231).
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Communication
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