Enantioselective total syntheses of (-)-taiwaniaquinone H and (-)-taiwaniaquinol B by iridium-catalyzed borylation and palladium-catalyzed asymmetric α-arylation

Article abstract of DOI:10.1021/ja110215b

We report a concise, enantioselective total synthesis of (-)-taiwaniaquinone H and the first enantioselective total synthesis of (-)-taiwaniaquinol B by a route that includes asymmetric palladium-catalyzed α-arylation of a ketone with an aryl bromide that

Full text of DOI:10.1021/ja110215b

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Enantioselective Total Syntheses of (-)-Taiwaniaquinone H and
(-)-Taiwaniaquinol B by Iridium-Catalyzed Borylation and
Palladium-Catalyzed Asymmetric R-Arylation
Xuebin Liao, Levi M. Stanley, and John F. Hartwig*
Department of Chemistry, University of Illinois, 600 South Mathews Avenue, Urbana, Illinois 61801-3602, United States
S Supporting Information
b
that eliminates this challenge is to prepare the material by a ring-
ABSTRACT: We report a concise, enantioselective total
synthesis of (-)-taiwaniaquinone H and the first enantiose-
lective total synthesis of (-)-taiwaniaquinol B by a route that
includes asymmetric palladium-catalyzed R-arylation of a
ketone with an aryl bromide that was generated by sterically
controlled halogenation via iridium-catalyzed C-H boryla-
tion. This asymmetric R-arylation creates the benzylic
quaternary stereogenic center present in the taiwani-
aquinoids. The synthesis was completed efficiently by
developing a Lewis acid-promoted cascade to construct
the [6,5,6] tricyclic core of an intermediate common to
the synthesis of a number of taiwaniaquinoids. Through
the preparation of these compounds, we demonstrate the
utility of constructing benzylic quaternary stereogenic cen-
ters, even those lacking a carbonyl group in the R-position,
by asymmetric R-arylation.
contractive derivatization of enantioenriched terpenes. Alvarez-
Manzaneda and co-workers prepared (-)-taiwaniaquinone G (1),22
(-)-taiwaniaquinone H (2), and (-)-dichroanone (3) in 15 or
16 steps from (þ)-sclareolide,23 and Gademann and co-workers
prepared 2 in 13 steps from methyl dehydroabiate.25 Recently,
Alvarez-Manzaneda and co-workers reported the syntheses of
(-)-taiwaniaquinone A (4) in 15 steps and (-)-taiwaniaqui-
none F (5) in 16 steps from (þ)-podocarpa-8(14)-en-13-one.30
To date, only two enantioselective total syntheses of taiwani-
aquinoids from achiral or racemic starting materials have been
reported. McFadden and Stoltz reported an 11-step synthesis of
(þ)-dichroanone (ent-3) in which the quaternary stereogenic
center was set by an asymmetric Tsuji allylation.17 Recently,
Node and co-workers employed an enantioselective intramole-
cular Heck reaction to complete the total syntheses of (-)-
dichroanal B (6) in 12 steps, 3 in 14 steps, and 2 in 15 steps
beginning with a tetrasubstituted arene.24
Recently, our group reported asymmetric R-arylations of
ketones to form products containing quaternary benzylic
stereogenic centers with high enantioselectivities.31 Although
the taiwainaquinoids do not contain a carbonyl group R to the
benzylic stereogenic center, we envisioned that asymmetric
R-arylation could be used to construct this center and that the
ketone function could be integral to creation of the [6,5,6]
tricyclic core. Further, we envisioned that the aryl electrophile for
the proposed R-arylation process could be generated from a
simple arene by a sterically controlled iridium-catalyzed borylation
and halogenation sequence developed by our group.32,33
Herein, we report concise enantioselective total syntheses of
(-)-taiwaniaquinone H (2) and (-)-taiwaniaquinol B (7) from
simple achiral and racemic reactants through this halogenation
process and an asymmetric R-arylation for the first time in the
synthesis of a natural product. A Lewis acid-promoted cascade
then establishes the unusual [6,5,6] tricyclic core.
he taiwaniaquinoids are a family of unusual diterpenoids
T
possessing a [6,5,6]-abeo-abietane skeleton that was unknown
in nature prior to 1995.1-7 Each member of this family contains a
benzylic quaternary stereogenic center (Figure 1). Studies of the
biological activities of taiwaniaquinoids are ongoing, but pre-
liminary data have indicated that some members of this family
exhibit antitumor activities.8-11 The structural features and the
biological activities of these compounds have led many groups to
report total and formal syntheses of the taiwaniaquinoids.11-25
However, the majority of these syntheses have targeted racemic
versions of this class of natural products.
Asymmetric syntheses of the taiwaniaquinoids are challenging
because of the limited number of enantioselective reactions that
establish quaternary stereogenic centers.26-29 One approach
Scheme 1 illustrates the strategy we envisioned to achieve the
enantioselective total syntheses of 2 and 7. Both molecules would
be accessible from the same intermediate, tetrahydrofluorene 8,
by demethylation and oxidation procedures. We considered that
the tricyclic core of tetrahydrofluorene 8 could be formed from
epoxide 9 by a formal intramolecular addition of the electron-rich
arene ring to the epoxide unit. Epoxide 9 would be derived from
R-aryl ketone 10, which would be generated by our palladium-
catalyzed asymmetric R-arylation of ketones.
Received: November 13, 2010
Published: January 26, 2011
Figure 1. Representative taiwaniaquinoids.
r
2011 American Chemical Society
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Scheme 1. Retrosynthetic Analysis for the Syntheses of
Scheme 3. Synthesis of Tetrahydrofluorene 8
(-)-Taiwaniaquinone H (2) and (-)-Taiwaniaquinol B (7)
The synthesis of the key tetrahydrofluorene intermediate 8
was accomplished in five steps from enantioenriched ketone 14
(Scheme 3). Acid-promoted hydrolysis of ketone 14 followed
by deformylation of the resulting β-ketoaldehyde in the presence
of aqueous sodium hydroxide provided deprotected ketone 15
in 91% yield over two steps. Dimethylation of 15 with methyl
iodide using sodium bis(trimethylsilyl)amide (NaHMDS) as
the base formed tetrasubstituted cyclohexanone 10 in 86%
yield.
Scheme 2. One-Pot Synthesis of Aryl Bromide 12a
a B2pin2 = bis(pinacolato)diboron; dtbpy =4,40-di-tert-butylbipyridine.
In the forward direction, the first step of the synthesis required
aryl bromide 12. Under traditional conditions for electrophilic
aromatic substitution, the known resorcinol derivative 1334
undergoes bromination at the position located ortho to the
two methoxy groups.16 To overcome this electronic bias, we used
a one-pot, two-step sequence to prepare aryl bromide 12 from 13
by the combination of a sterically controlled iridium-catalyzed
borylation and a subsequent bromination of the aryl boronate
ester with copper(II) bromide (Scheme 2).32 This method
provided aryl bromide 12 in 75% yield on a multigram scale.
Access to aryl bromide 12 enabled us to explore the key
enantioselective R-arylation. The reaction of aryl bromide 12
with 2,2,6-trimethylcyclohexanone did not generate the R-aryla-
tion product in the presence of a catalyst generated from
Pd(dba)2 and (R)-Segphos or (R)-Difluorophos. However, the
reaction of aryl bromide 12 with the 2-methylcyclohexanone
derivative 1135,36 in the presence of the combination of Pd(dba)2
and (R)-Difluorophos as catalyst (10 mol %) formed R-aryl
ketone 14 in 80% yield with 94% ee (eq 1).37
The absolute configuration of the stereogenic center in these
products was established by iodination of 15. The reaction
of 15 with iodine and silver sulfate formed diiodide 16 (eq 2).
Single-crystal X-ray diffraction of the major diastereomer of
16 enabled the assignment of the absolute configuration as
(2R,6S)-16 (see Figure S1 in the Supporting Information). Thus,
the enantioselective R-arylation of ketone 11 conducted with
(R)-Difluorophos and Pd(dba)2 generated (R)-14 and created
the appropriate enantiomer for preparation of (-)-taiwaniaquinone
H (2) and (-)-taiwaniaquinol B (7).
Attempts to convert ketone 10 to epoxide 9 by Corey-
Chaykovsky epoxidation using the common sulfur ylide dimethyl-
sulfoxonium methylide38,39 ledtorecoveryof10, even under forcing
conditions (80 °C). We presumed that this lack of reactivity resulted
from the steric hindrance surrounding the ketone functionality in 10.
Thus, we attempted a Corey-Chaykovsky epoxidation of ketone 10
using the smaller and more reactive sulfur ylide dimethylsulfonium
methylide.39,40 This reaction formed epoxide 9 in 95% yield with
>15:1 diastereoselectivity.
Some Lewis acids are known to promote the rearrangement of
epoxides to carbonyl compounds.41-45 We tested the ability of
such Lewis acids to initiate the cascade shown in Scheme 3, in
which epoxide 9 would form tetrahydrofluorene 8 via rearrange-
ment of the epoxide to the aldehyde. This aldehyde would then
be attacked by the electron-rich arene in the presence of a Lewis
acid to form the corresponding alcohol, which could undergo
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COMMUNICATION
Scheme 4. Synthesis of (-)-Taiwaniaquinone H (2)a
10 steps, and the first enantioselective total synthesis of (-)-
taiwaniaquinol B was completed in 11.9% overall yield in just
12 steps. Two catalytic protocols reported by our group, a one-
pot meta bromination of 2-isopropyl-1,3-dimethoxybenzene by
iridium-catalyzed borylation followed by reaction of the resulting
arylboronate with copper(II) bromide and a palladium-catalyzed
enantioselective R-arylation, were used in early steps on multi-
millimolar scales. The syntheses were completed efficiently by
developing a Lewis acid-promoted cascade to construct the
[6,5,6] tricyclic core of an intermediate common to the synthesis
of a number of taiwaniaquinoids. Finally, we emphasize that the
quaternary stereogenic center in the taiwaniquinoids bears no
carbonyl group in the R-position but is readily set by the
asymmetric R-arylation and that the ketone functionality serves
as a key point of reaction to complete the syntheses. Thus, the
enantioselective R-arylation of ketones should be considered as a
strategic method for establishing quaternary benzylic stereogenic
centers for complex-molecule synthesis. Further studies to
increase the scope of this enantioselective process are ongoing.
a Salcomine = N,N0-bis(salicylidene)ethylenediaminocobalt(II).
Scheme 5. Synthesis of (-)-Taiwaniaquinol B (7)
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental details, charac-
b
terization data, H and 13C NMR spectra, and crystallographic
1
data for 16 (CIF). This material is available free of charge via the
Internet at http://pubs.acs.org.
elimination to form the target tetrahydrofluorene 8. After testing
a series of Lewis acid catalysts for this sequence (see Table S1 in
the Supporting Information), we found that treatment of epoxide
’ AUTHOR INFORMATION
Corresponding Author
jhartwig@illinois.edu
9 with BF3 OEt2 or a Bi(III) salt generated tetrahydrofluorene 8
3
in good yield. The cascade promoted by BF3 OEt2 formed
3
tetrahydrofluorene 8 in up to 75% yield; however, the yields of
this reaction varied from 50 to 75%. Slightly lower yields were
observed for the formation of tetrahydrofluorene 8 from epoxide
9 in the presence of a Bi(III) salt as the Lewis acid, but this
reaction was less sensitive to variations in temperature. Ulti-
mately, we conducted this cascade promoted by 20 mol % BiCl3
to generate tetrahydrofluorene 8 in 64% yield.
’ ACKNOWLEDGMENT
We thank the NIH for financial support of this work (GM-58108
to J.F.H. and GM84584 to L.M.S.), Zhijian Liu for contributions to
early steps in the synthesis, Johnson-Matthey for gifts of iridium and
palladium salts, and Allychem and BASF for gifts of bis(pinacolato)-
diboron.
The synthesis of (-)-taiwaniaquinone H (2) was completed
according to methods developed by Trauner and co-workers
for the synthesis of (()-taiwaniaquinone H.16 Selective mono-
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