Tandem intramolecular hydroalkoxylation-hydroarylation reactions: Synthesis of enantiopure benzofused cyclic ethers from the chiral pool

Article abstract of DOI:10.1002/chem.200800312

A highly efficient and general method for the diastereoselective synthesis of benzo-fused eight-membered carbo- and heterocycles was studied. The method is based on a new tandem gold- or platinum catalyzed hydroalkoxytion- hydroarylation reaction. The use

Full text of DOI:10.1002/chem.200800312

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DOI: 10.1002/chem.200800312
Tandem Intramolecular Hydroalkoxylation–Hydroarylation Reactions:
Synthesis of Enantiopure Benzofused Cyclic Ethers from the Chiral Pool
JosØ Barluenga,* Amadeo Fernµndez, Amaya Satrfflstegui, Alejandro DiØguez,
FØlix Rodríguez, and Francisco J. FaÇanµs[a]
Nowadays, one of the main challenges that organic chem-
ists face is the production of architecturally complex mole-
cules in facile, efficient, and economical ways.[1] In this con-
text, concurrent tandem catalysis provides a means to im-
prove chemical transformations and thus synthetic efficien-
cy.[2] Accordingly, our research group has recently developed
some new tandem catalytic reactions for the synthesis of at-
tractive skeletal cores from simple starting materials.[3,4]
Having in mind the superb ability of gold and platinum cata-
lysts to accomplish otherwise difficult hydroalkoxylation[5]
and hydroarylation[6] reactions of unsaturated substrates,[7]
we were drawn to the possibility of combining these two dif-
ferent reactions in a single synthetic operation.[8] We envis-
aged that starting from benzyl-substituted alkynol deriva-
tives 1, an initial intramolecular hydroalkoxylation reaction
would provide the enol ethers 2. This substrate would be
disposed to undergo a catalytic intramolecular hydroaryla-
tion reaction to give interesting benzo-fused ethers
(Scheme 1).
Our final objective was to find the appropriate conditions
to perform both steps in a one-pot approach by using a
single catalyst. Also appealing was the possibility of apply-
ing this reaction for the modification of some natural prod-
ucts to generate enantiomerically pure compounds with po-
tential biological activity. Herein, we report our findings in
this field.
To checkthe feasibility of the proposed tandem catalytic
reaction, the initial proof-of-concept studies were performed
by using the model dibenzyl-substituted alkynol 1a as start-
ing material. Thus, we treated compound 1a with 5 mol%
of several gold, platinum, and silver complexes in 1,2-di-
chloroethane as solvent at room temperature (Table 1).
When [Ph3PAuCl] was used as catalyst, the reaction did not
proceed, and the starting compound 1a was quantitatively
recovered after 24 h (Table 1, entry 1). However, we found
that the desired ether 3a was produced in 96% yield as a
single diastereoisomer when the reaction was performed
with the cationic gold(I) catalyst generated in situ from
Table 1. Cycloisomerization reactions of the alkynol 1a with several
gold, platinum and silver catalysts.
Scheme 1. Concept of the tandem catalytic hydroalkoxylation–hydro-
ACHTREUNGarylation reaction for the synthesis of benzofused bicyclic ethers.
Entry
Catalyst (MLn)
[Ph3PAuCl]
[Ph3PAuCl]/AgOTf
AgOTf
AuCl3
t [h]
Yield [%][a]
1
2
3
4
5
6
7
G
24
1
24
6
24
1
1
0
96
AHCTREUNG
<10[b]
50[c]
0
[a] Prof. Dr. J. Barluenga, A. Fernµndez, A. Satrfflstegui, Dr. A. DiØguez,
Dr. F. Rodríguez, Dr. F. J. FaÇanµs
G
Instituto Universitario de Química Organometµlica “Enrique Moles”
Unidad Asociada al C.S.I.C.Universidad de Oviedo
Juliµn Clavería, 8; 33006 Oviedo (Spain)
U
94
92
Fax : (+34)985103450
E-mail: barluenga@uniovi.es
[a] Yield of isolated product based on the starting alkynol 1a. [b] Deter-
mined by H NMR analysis of the crude reaction mixture; the starting al-
1
Supporting information for this article is available on the WWW
under http://www.chemistry.org or from the author.
kynol 1a was the major product (ca. 90%). [c] 42% of the starting alky-
nol 1a was recovered.
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[Ph3PAuCl] and AgOTf (Table 1, entry 2). To ensure that
the silver complex was not responsible for the catalytic pro-
cess, we carried out an experiment with 5 mol% AgOTf
(Table 1, entry 3). However, under these conditions, com-
pound 3a was generated in less than 10% yield after 24 h at
room temperature. Next, we tried the reaction with the
higher valent gold complex [AuCl3] (Table 1, entry 4). This
complex turned out to be less active than the cationic
gold(I) complex mentioned above; the product 3a was iso-
lated in 50% yield after 6 h.
The use of [(cod)PtCl2] (cod=1,5-cyclooctadiene) was
completely ineffective and the starting material was recov-
ered after 24 h at room temperature (Table 1, entry 5). How-
ever, the use of the cationic platinum(II) complex formed in
situ by mixing [(cod)PtCl2] and AgOTf gave excellent re-
sults, allowing the complete transformation of alkynol 1a
into bicyclic compound 3a (94% yield) after only 1 h
(Table 1, entry 6). Finally, the platinum(IV) complex PtCl4
also catalyzed this process to give 3a in 92% yield after 1 h
(Table 1, entry 7).
also a CH2 group (Table 2, entries 4–10) or a nitrogen atom
(Table 2, entry 11). Thus, different eight-membered carbocy-
cles and oxygen- and nitrogen-containing heterocycles 3 are
readily obtained in high yield and as single diastereoisomers.
The reaction can also be performed with alkynols 1c and 1e
containing internal triple bonds (Table 2, entries 3 and 5).
The R1 group attached to the carbon atom containing the
hydroxy group could also be varied (Table 2). Structural as-
signments of compounds 3 were based on a series of NMR
studies. Finally, it should be noted that although the prod-
ucts shown in Table 2 were obtained by reactions performed
with [Ph3PAuCl]/AgOTf as catalyst, essentially the same re-
sults were observed by using [(cod)PtCl2]/AgOTf or PtCl4 as
catalysts.
The importance of natural products as lead structures for
the generation of small-molecule libraries has been empha-
sized in recent years.[9] In this context, we thought that a-hy-
droxy- and a-amino acids were ideal templates for the syn-
thesis of potentially bioactive compounds by applying the
tandem catalytic reaction described above. Thus, by conven-
tional organic chemistry reactions, d-lactate and several l-
amino esters were easily transformed into the chiral alkynol
derivatives 1l–r (Table 3). Further treatment of these com-
All these experiments allowed us to determine that both
cationic PtII and AuI, and also PtIV complexes were appro-
priate catalysts to perform the synthesis of benzofused
bicycloACHTREUNG[3.3.1]nonanes such as 3a. With proof-of-concept es-
tablished, the scope of this catalytic process was evaluated
by changing the nature of the substituents of the starting al-
kynol derivative 1 at several points. The results are summar-
ized in Table 2.
Table 3. Enantiopure benzofused bicycloACHTRE[UGN 3.3.1]nonanes.
Table 2. Benzofused bicyclo
ACHTRE[UNG 3.3.1]nonanes 3 by tandem hydroalkoxyla-
tion–hydroarylation reactions of the alkynol derivatives 1.[a]
Entry
1
R1
R2
R3
R4
X
3
Yield
[%][b]
Entry
1
Ar
R1
R
3
R2
R3
Yield
[%][a]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1 f
1g
1h
1i
Bn
3-MeOBn
Bn
Bn
H
OMe
H
H
H
OMe
Me
OMe
Me
H
H
H
H
H
H
H
H
H
H
H
Ph
H
Ph
H
H
H
H
H
H
O
O
O
3a
3b
3c
3d
3e
3 f
3g
3h
3i
96
96
92
95
92
88
90
70
82
88
90
1
2
3
4
5
6
7
1l
Ph
H
Ph
H
Ph
H
H
–
–
Me
Me
Bn
3l
H
OMe
H
H
OMe
H
H
H
H
H
H
H
95
95
93
88
95
66
93
1m
1n
1o
1p
1q
1r
3-MeOC6H4
Ph
Ph
3m
3n
3o
3p
3q
3r
CH2
CH2
CH2
CH2
CH2
CH2
CH2
NTs
Bn
3-MeOBn
3-MeBn
H
3-MeOC6H4
Ph
iBu
iBu
1-Naph[b]
H
-(CH)4-
9
10
11
Et
[c]
1j
1k
1-NaphCH2
Bn
-(CH)4-
3j
3k
[a] Yield based on starting alkynol 1. [b] 1-Naph=1-naphthyl.
H
H
[a] Reactions stirred at room temperature till consumption of the starting
material (1–8 h). [b] Yield of isolated product based on starting alkynol
1. [c] 1-NaphCH2 =1-naphthylmethyl.
pounds with 5 mol% PtCl4 in dichloroethane at reflux readi-
ly afforded the a-hydroxy acid derivatives 3l,m or the a-
amino acid derived products 3n–r in very high yield as
single diastereomers and enantiomers. As shown, this proto-
col allows the synthesis of enantiomerically pure bicyclo-
Interestingly, for example, the chain connecting the hy-
droxyl group and the alkyne of starting compound 1 may
contain not only an oxygen atom (Table 2, entries 1–3), but
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Enantiopure Benzofused Cyclic Ethers
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signments of these new compounds were based on a series
of NMR studies. Additionally, the structures of compounds
3n, 3o, and 3q were confirmed by single-crystal X-ray struc-
ture analysis.[10] Surprisingly, we observed the opposite chiral
induction when starting from alkynols 1l,m, derived from d-
lactate, or from alkynols 1n–r, derived from l-amino acids.
A tentative mechanism for the formation of compounds 3,
based on a tandem sequence involving a 6-exo-cycloisomeri-
zation reaction followed by an intramolecular hydroaryla-
tion process, is presented in Scheme 2. Thus, the reaction is
room temperature. After 1 h, complete conversion to 3d
was observed.
An intriguing question related to the mechanism of this
process is the identity of the catalytic species responsible for
the two catalytic cycles proposed in Scheme 2. In principle,
both Lewis and Brønsted acids could catalyze the hydroal-
koxylation and hydroarylation reactions. Traces of Brønsted
acids could be present in the reaction media coming from
the platinum or gold complexes (or the solvent), and these
protic acids could be the responsible for both or at least one
of the catalytic cycles proposed in Scheme 2.[11] To shed light
on this issue, the alkynol 1d was subjected to a range of re-
action conditions. No reaction was observed in the absence
of platinum or gold complexes or by treatment of 1d with
Brønsted acids, which demonstrates the necessity of the
platinum or gold complexes at least for the hydroalkoxyla-
tion reaction. To eliminate the possibility of competing
Brønsted acid catalysis in the second catalytic cycle (the hy-
droarylation reaction), we performed some control experi-
ments by using a non-poisoning base. Thus, when compound
1d was allowed to react with 5 mol% PtCl4 in a dichlorome-
thane solution containing 2.5 mol% of the strong phosphor-
ine base BEMP (2-tert-butylimino-2-diethylamino-1,3-di-
methyl-perhydro-1,3,2-diazaphosphorine), we observed the
formation of the expected product 3d after 1 h at room tem-
perature. Additionally, we performed an experiment in
which we treated 1d with 5 mol% PtCl4 in dichloromethane
at À208C and once we observed the complete conversion
(by GC-MS
) to the intermediate iso-2d, we added
2.5 mol% BEMP. The solution was warmed to room tem-
perature, and after 1 h complete conversion to the final
product 3d was observed. All these results suggest that re-
sidual Brønsted acids are not responsible, because these
would be quenched by BEMP (at 2.5 mol%). Accordingly,
we believe that the gold or platinum catalytic species are in-
volved in both catalytic cycles proposed in Scheme 2.[12]
To verify the stereochemistry observed in the products de-
rived from d-lactate and l-amino acids (see Table 2), we fo-
cused on the structure of the corresponding intermediate 6.
Thus, for d-lactate derived products 3l,m we suppose that
the reactions proceed via the intermediates 6l,m
(Scheme 2). As shown, in this structure the methyl group is
placed in a pseudo-equatorial position. However, to explain
the formation of compounds 3n–r, derived from l-amino
acids we suppose that the reactions proceed via intermedi-
ates 6n–r, in which the R group is placed in a pseudo-axial
position.[13]
In summary, we have developed a highly efficient and
general method for the diastereoselective synthesis of
benzo-fused eight-membered carbo- and heterocycles. The
method is based on a new tandem gold- or platinum-cata-
lyzed hydroalkoxylation–hydroarylation reaction. The
tandem sequence described allows the straightforward and
efficient synthesis of complex final products. The number of
points of diversity present in the reaction products, together
with the simplicity of the starting materials, makes this
tandem reaction a powerful method for both library genera-
Scheme 2. Proposed mechanism for the formation of benzofused bicyclo-
ACHTREUNG[3.3.1]nonanes 3 from alkynols 1.
initiated by coordination of the metallic complex to the
triple bond of the starting alkynol 1 to form intermediate 4.
Intramolecular addition of the hydroxy group to the internal
carbon of the triple bond generates 5. Protodemetalation of
the latter affords the enol ether 2 and releases the catalytic
species. Once enol ether 2 is formed, it enters the second
catalytic cycle. Thus, after an initial coordination of the cata-
lyst to the double bond of the enol ether 2, the oxonium in-
termediate 6 is formed. Further nucleophilic attackof the
phenyl group affords the intermediate 7. Interestingly, the
stereochemistry of all new stereocenters is fixed by the axial
position of the benzyl group required for the cyclization
step. Finally, from 7, a rearomatization and a protodemeta-
lation step lead to the final product 3, regenerating the cata-
lytic species.
The role of enol ethers 2 as intermediates of the reaction
was supported by the isolation of enol ether iso-2d (see
Scheme 2) when an experiment was performed with alkynol
1d in dichloromethane at À208C and using 5 mol% PtCl4 as
catalyst. To corroborate the formation of 3d from iso-2d we
treated the latter with 5 mol% PtCl4 in dichloromethane at
Chem. Eur. J. 2008, 14, 4153 – 4156
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J. Barluenga et al.
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pure benzofused cyclic ethers reported in this workis a
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Experimental Section
Experimental details and NMR spectroscopic and mass spectrometric
data for the experiments reported in Tables 1–3 are given in the Support-
ing Information.
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Acknowledgements
We gratefully acknowledge financial support from the DGICYT
(CTQ2004-08077-C02-01/BQU and CTQ2007-61048/BQU), FICYT
(grant to A. D.), MEC (grant to A. S. and “Ramón y Cajal” contract to
F.R.). We also thankDr Angel L. Suµrez for his help in the X-ray struc-
ture determination.
Keywords: cyclization
·
domino reactions
·
gold
·
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www.ccdc.cam.ac.uk/data_request/cif.
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Received: February 20, 2008
Published online: April 2, 2008
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