Highly efficient gold-catalyzed synthesis of dibenzocycloheptatrienes

Article abstract of DOI:10.1002/chem.201402015

Dibenzocycloheptatrienes are obtained by a gold-catalyzed 7-exo-dig hydroarylation protocol in a highly efficient manner. The gold-catalyzed reaction usually gives the products in high yields and excellent selectivity. This procedure provides an easy and

Full text of DOI:10.1002/chem.201402015

DOI: 10.1002/chem.201402015
Full Paper
&
Gold Catalysis
Highly Efficient Gold-Catalyzed Synthesis of
Dibenzocycloheptatrienes
Daniel Pflꢀsterer,[a] Eva Rettenmeier,[a] Severin Schneider,[a] Edgar de Las Heras Ruiz,[a]
Matthias Rudolph,[a] and A. Stephen K. Hashmi*[a, b]
Abstract: Dibenzocycloheptatrienes are obtained by a gold-
catalyzed 7-exo-dig hydroarylation protocol in a highly effi-
cient manner. The gold-catalyzed reaction usually gives the
products in high yields and excellent selectivity. This proce-
dure provides an easy and efficient access to dibenzocyclo-
heptanoids, which are an interesting and unique class of
natural products. This was underlined by the first total syn-
thesis of reticuol.
Introduction
The gold-catalyzed hydroarylation of alkynes is known as an
important and powerful tool for organic synthesis.[1] While for
the intramolecular reaction with heteroaromatic systems as nu-
cleophiles,[2] a high flexibility regarding the ring size is reported
(even eight-membered rings can be obtained), only one
report[3] on the formation of larger ring sizes can be found if
nonheterocyclic aromatic rings are applied as nucleophiles.[4]
This topic attracted our attention owing to the importance
of the dibenzocycloheptane motif, which could be addressed
by a gold-catalyzed cyclization of biaryls bearing a homopro-
pargylic tether. Inspired by former work of Fꢁrstner et al., who
applied alkynyl-substituted biaryl systems for the synthesis of
phenanthrenes,[5] we assumed that it might be possible to de-
velop conditions to synthesize dibenzocycloheptatrienes by
a gold-catalyzed 7-exo-dig hydroarylation reaction. The ad-
dressed structural motif can be found in many pharmacologi-
cally active compounds exhibiting interesting biological activi-
ties. One example is allocolchicine, which is active against
many cancer cell lines.[6] In the last years, several natural prod-
ucts belonging to the class of dibenzocycloheptanoids have
been isolated from different sources.[7] Figure 1 depicts, as se-
lected representatives, tenuifolin,[7d,f] which shows antiprolifera-
tive activity against tumor cell line DU145, the strongly related
reticuol as an inhibitor of cytochrom P450 (CYP3A4),[7b,i]
subavenoside E,[7c] showing inhibitory activity against a-gluco-
Figure 1. Examples of the dibenzocycloheptane core in natural products.
sidase type IV from Bacillus stearothermophilus, dibenzocyclo-
heptadiene sihydroisosubamol,[7c] and subamol.[7a,e]
Besides their biological activity, these compounds are also
interesting owing to their dynamic stereochemistry. Compound
4 exists as a mixture of two interconverting diastereomers,[7c]
which was shown by in situ NOESY-NMR measurements.[8]
Regarding the dibenzocycloheptanoids, only 2 was already
synthesized.[7f] This fact inspired us to develop a methodology
for the highly efficient synthesis of dibenzocycloheptatrienes
to provide an easy access to this class of natural products.
Results and Discussion
[a] D. Pflꢀsterer, E. Rettenmeier, S. Schneider, E. de Las Heras Ruiz, M. Rudolph,
Prof. Dr. A. S. K. Hashmi
As test substrate homopropargyl-substituted biaryl 7a was se-
lected (Table 1). To control a selective attack of the lower ben-
zene part, donating methoxy groups were used to prevent
a competing 5-exo/6-endo cyclization. We started the optimiza-
tion of the reaction conditions with [IPrAuNTf2] in CD2Cl2 with
a catalyst loading of 5 mol%. Complete conversion was ob-
served after 5 h at room temperature, accompanied by an ex-
cellent combined yield (entry 1). Unfortunately, besides the
original hydroarylation product 9a (64%), isomerization of the
Organisch-Chemisches Institut
Ruprecht-Karls-Universitꢀt Heidelberg
Im Neuenheimer Feld 270, 69120 Heidelberg (Germany)
E-mail: hashmi@hashmi.de
[b] Prof. Dr. A. S. K. Hashmi
Chemistry Department, Faculty of Science
King Abdulaziz University, Jeddah 21589 (Saudi Arabia)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201402015.
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catalyst (entries 8 and 9). The use of only 0.1 mol%
catalyst did not lead to full conversion after 17 h, but
still 8a was formed selectively in a high yield of 87%
(entry 10). To demonstrate that the acid itself cannot
catalyze the hydroarylation step, the reaction was
carried out with 5 mol% of HNTf2, showing not even
traces of product after 2 days (entry 12). The control
experiment with AgNTf2 as catalyst gave the same
result (entry 11).
Table 1. Optimization of the reaction conditions.
Entry[a] Catalyst
Acid
t
Yield 9a (8a)
[5 mol%] [h] [%][b]
After optimizing the catalyst system, we turned
our focus on the evaluation of the scope of the reac-
tion (Scheme 1). The optimized conditions were used
on a 0.2 mmol scale. As expected, compound 7a was
nicely converted into the desired product 8a after
45 min in 99% yield. Next, we investigated the influ-
ence of a substituent in 3-position of the arene
system bearing the alkynyl tether. 7b containing
a fluoro substituent in this position gave 8b in 99%
yield with a slightly prolonged reaction time, whereas
7c with a methoxy group was converted completely
to 8c after 30 min, albeit in a slightly reduced yield
of 79%. Fortunately, 8c was the only product ob-
served, which is quite remarkable if one considers
the electron-donating properties of the methoxy
group that could also induce an attack at the 4-posi-
1
2
3
4
5
6
7
8
9
[IPrAuNTf2] (5 mol%)
[XPhosAu(CH3CN)]SbF6 (5 mol%)
–
–
–
–
–
–
–
5.0 98 (34)
4.0 84 (40)
0.1 99 (99)
1.5 99 (57)
0.2 93 (93)
0.1 99 (99)
5.0 99 (60)
0.3 99 (99)
0.8 98 (98)
17 87 (87)
48 n.c.[c]
48 n.c.[c]
[(2,4-di-tBu-C6H3O)3PAu(PhCN)]SbF6 (5 mol%)
[(2,4-di-tBu-C6H3O)3PAuNTf2] (5 mol%)
[(2,4-di-tBu-C6H3O)3PAuCl]/AgSbF6 (5 mol%)
[(2,4-di-tBu-C6H3O)3PAu(PhCN)]SbF6 (2 mol%)
[(2,4-di-tBu-C6H3O)3PAu(PhCN)]SbF6 (0.5 mol%)
[(2,4-di-tBu-C6H3O)3PAu(PhCN)]SbF6 (1 mol%) HNTf2
[(2,4 di-tBu-C6H3O)3PAu(PhCN)]SbF6 (0.5 mol%) HNTf2
[(2,4-di-tBu-C6H3O)3PAu(PhCN)]SbF6 (0.1 mol%) HNTf2
10
11
12
AgNTf2
–
–
HNTf2
[a] Reactions were carried out with 0.05 mmol of substrate. [b] Yields were determined
by 1H NMR spectroscopy with tri-tert-butylbenzene as internal standard. The yield in
brackets corresponds to the yield of 8a. [c] n.c.=no conversion.
double bond delivered side product 8a (34%). This isomeriza-
tion is a known observation for the products of 7-exo-dig hy-
drofunctionalizations.[2h,9] Unfortunately, our attempts to fully
isomerize the primer product by shifting the solvent to more
acidic CDCl3 did not lead to the selective formation of 8a.
Thus, we considered a further variation of the ligand system to
induce further isomerization. We continued the screening of
catalysts with [XPhosAu(MeCN)]SbF6 (5 mol%), giving 84%
total yield but in low selectivity (40% of 8) after 4 h (entry 2).
To our delight, 5 mol% of the electron-poor gold catalyst
[(2,4-di-tBu-C6H3O)3PAu(PhCN)]SbF6 selectively furnished 8a in
99% yield after only 5 min (entry 3). The similar gold complex
tion of the upper arene moiety. The fluoro substituent in the
4-position of 7d did not lead to any changes compared to 7b
À
À
with NTf2 instead of SbF6 as counter ion was less successful,
showing a prolonged reaction time and again a mixture of
both products. While the overall yield was excellent (99%),
only 57% of 8a were formed (entry 4). The reaction with
5 mol% [(2,4-di-tBu-C6H3O)3PAuCl], in situ activated by AgSbF6,
needed slightly more time until complete conversion was
reached and also gave a lower yield of 93% (entry 5). With the
optimized catalytic system, we next evaluated the possibility
to decrease the catalyst loading. While 2 mol% of catalyst
showed no difference (entry 6), with 0.5 mol% of catalyst the
reaction time was prolonged to 5 h and the yield of 8a drop-
ped to 60% (entry 7). To reduce the catalyst loadings further,
we considered a non-coordinating acid as additive that could
support the isomerization step.
The addition of HNTf2 to a mixture of 8a and 9a gave com-
plete conversion to 8a after only 1 min. With this knowledge
in hand, we again tried to decrease the catalyst loading in the
presence of additional 5 mol% of HNTf2. By using this combi-
nation, the reaction could be conducted with 1 mol% (20 min,
99% 8a) and even with 0.5 mol (45 min, 98% 8a) of the gold
Scheme 1. Scope of the reaction. [a] The reaction was conducted with
2 mol% of catalyst. [b] The reaction was performed on a 0.5 mmol scale.
Chem. Eur. J. 2014, 20, 6752 – 6755
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in terms of reaction time and yield, and 8d was formed in
98% yield after 2 h. Interestingly, compound 7e bearing an ad-
ditional methoxy group attached to the nucleophilic ring
system needed 4 h for completion, but still 8e was obtained in
an excellent yield of 97%. The unsymmetrically substituted
substrate 7 f showed an even longer reaction time, yielding 8 f
in 73%. 7g containing the less donating methylenedioxy
moiety did not give complete conversion with 0.5 mol% of
catalyst; even with 2 mol% the reaction needed 72 h to pro-
ceed, furnishing 8g in 68% yield. For compound 7h, a mixture
of two products corresponding to an attack in para- (8h) or
ortho-position (8h’) of the methoxy group was obtained after
6 h. This reaction was also conducted with 2 mol% of catalyst,
giving the products in 55% overall yield in a ratio of 6:1 (8h/
8h’) from 7h.
Substrate 7i was also prepared and tested under the opti-
mized conditions. Similar molecules were successfully cyclized
to phenanthrenes with platinum or gold catalysts in earlier[4a,10]
and recent work,[3] but unfortunately no conversion was ob-
served (Scheme 2). Next, we tried to accelerate the reaction by
Scheme 3. First total synthesis of reticuol. Conditions: a) 10 (1.5 equiv),
Pd(OAc)2 (5.0 mol%), PPh3 (10 mol%), K2CO3 (4.0 equiv), DME/water 3:1,
808C, 13 h, 97%; b) DIBAL-H (2.0 equiv), abs. CH2Cl2, À908C, 2 h, 99%;
c) Bestmann–Ohira reagent (1.5 equiv), Cs2CO3 (3.0 equiv), abs. MeOH, 08C–
RT, 1 h, 92%; d) [(2,4-di-tBu-C6H3O)3PAu(PhCN)]SbF6 (2.0 mol%), HNTf2
(5.0 mol%), CH2Cl2, RT, 72 h, 68%; e) Pd2dba3 (2.0 mol%; dba=dibenzyli-
deneacetone), tBuXPhos (8 mol%), KOH (4.0 equiv), 1,4-dioxane/water 1:1,
1008C, 24 h, 94%; f) SeO2 (2.0 equiv), 1,4-dioxane/HCOOH 3:1, 2 h, then
NaBH4 (4.0 equiv), MeOH, 30 min, 74%.
with an overall yield of 42% (Scheme 3), which corresponds to
an average yield of 86% per step.
Scheme 2. Nonreacting substrate 7i.
Conclusion
In conclusion, we have developed a selective 7-exo-dig hydro-
arylation with aromatic nucleophiles. This reaction offers
a rapid access towards highly interesting dibenzocyclotrienes.
These compounds have great potential in the synthesis of sev-
eral natural products, as it was shown with the first total syn-
thesis of reticuol. In addition, continued studies regarding the
atropisomerism of these compounds are ongoing in our labo-
ratories and will be reported in due course.
conducting it at 808C in DCE with 5 mol% of [XPhosAu-
(CH3CN)]SbF6 (because of the superior heat stability of this cat-
alyst)[11] and 5 mol% HNTf2 as additive. Even after several days
of heating, only traces of the desired product were observed
by GC-MS analysis. The major product showed a molecular ion
peak with m/z=274, strongly supporting simple water addi-
tion to the alkyne. Under anhydrous conditions, even after sev-
eral days of heating, GC-MS and NMR analysis showed solely
starting material. Unfortunately we do not have an explanation
for the failure of this reaction.
Acknowledgements
To demonstrate the great potential of this transformation,
the first total synthesis of reticuol was accomplished. This natu-
ral product was isolated from Cinnamomum Burmani and
showed inhibition of CYP3A4[7i] and from Cinnamomum reticu-
latum.[7b] Biphenyl 12g was synthesized from the boronic acid
10 and aryl bromide 11 g in a Pd-catalyzed Suzuki–Miyaura
cross coupling reaction in an excellent yield of 97%. 13g was
then smoothly obtained after DIBAHL-H (diisobutylaluminium
hydride) reduction and subsequent Seyferth–Gilbert homolo-
gation in 91% overall yield. In the key step, the tetracyclic core
of 8g was synthesized by following the gold-catalyzed hydro-
arylation strategy in 68% yield. The phenolic hydroxyl group
was then introduced by a Pd-catalyzed hydroxylation with
KOH,[12] furnishing the phenol in an excellent yield of 94%. Re-
ticuol was finally obtained after allylic oxidation of the olefinic
methyl group. In total, reticuol was synthesized in six steps
The authors thank Umicore AG & Co. KG for the generous don-
ation of gold salts.
Keywords: dibenzocycloheptanoids · gold · hydroarylation ·
natural products · total synthesis
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Received: February 3, 2014
Published online on April 25, 2014
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