Gold- or platinum-catalyzed cascade processes of alkynol derivatives involving hydroalkoxylation reactions followed by prins-type cyclizations

Article abstract of DOI:10.1002/chem.200900856

An efficient method for the synthesis of [3.3.1]bicyclic compounds from easily available alkynol derivatives has been developed. The reaction is based on a gold- or platinum-catalyzed tandem process that involves an intramolecular hydroalkoxylation of a t

Full text of DOI:10.1002/chem.200900856

DOI: 10.1002/chem.200900856
Gold- or Platinum-Catalyzed Cascade Processes of Alkynol Derivatives
Involving Hydroalkoxylation Reactions Followed by Prins-Type Cyclizations
Josꢀ Barluenga,* Amadeo Fernꢁndez, Alejandro Diꢀguez, Fꢀlix Rodrꢂguez, and
Francisco J. FaÇanꢁs[a]
Abstract: An efficient method for the
synthesis of [3.3.1]bicyclic compounds
from easily available alkynol deriva-
tives has been developed. The reaction
is based on a gold- or platinum-cata-
lyzed tandem process that involves an
intramolecular hydroalkoxylation of a
triple bond followed by a Prins-type
cyclization. The reaction has been car-
ried out with differently substituted al-
kynol derivatives and oxygen-, nitro-
gen-, and carbon-centered nucleophiles.
The incorporation of halogen atoms as
nucleophiles and elimination reactions
has also been studied. Enantiomerically
pure [3.3.1]bicyclic systems were easily
synthesized from the chiral pool.
Keywords: bicyclic systems · cas-
cade reactions · catalytic synthesis ·
cyclization · gold · platinum
Introduction
dition of nucleophiles. When the nucleophile is contained in
the structure of the starting alkyne, interesting carbo- and
heterocyclic compounds may be obtained through intramo-
lecular additions to the triple bond. In this sense, various in-
ternal nucleophiles, such as alkenyl-,[4] aryl-,[5] 1,3-dicarbon-
yl-,[6] oxygen-,[7] and nitrogen-containing functions,[8] have
been used.
The increasing demand for molecules with unprecedented
diversity requires the development of new methods for the
efficient and stereocontrolled construction of architecturally
complex structures from simple starting materials. To this
end, tandem reactions (domino or cascade reactions) have
emerged as very attractive tools as they allow several bond-
forming and/or -cleaving events to occur in one synthetic op-
eration, thus minimizing the costs and waste associated with
one-reaction/one-vessel approaches.[1] Also, considerable
focus has been directed towards organotransition-metal-cat-
alyzed processes for the construction of complex cyclic
structures owing to the ability of metallic species to promote
reactions which would require many steps by traditional
procedures.[2] In this context, gold and platinum salts or
complexes have become very promising catalysts in organic
chemistry due to their high activity and the mild reaction
conditions required to perform nonconventional transforma-
tions.[3] One of the most interesting features of these cata-
lysts is their ability to activate alkynes and promote the ad-
Following our interest in the development of new tandem
reactions promoted by
a
single catalyst[9] (concurrent
tandem catalysis),[10] we envisaged a strategy that employs
readily available alkynol derivatives for the construction of
interesting bicyclic compounds (Scheme 1).[11] The sequence
would involve an initial exo addition of the hydroxy group
to the triple bond to give an enol ether. If this enol ether
contains an allyl moiety at an appropriate position and in
the presence of a suitable nucleophile, it could participate in
[a] Prof. Dr. J. Barluenga, A. Fernꢀndez, Dr. A. Diꢁguez,
Dr. F. Rodrꢂguez, Dr. F. J. FaÇanꢀs
Instituto Universitario de Quꢂmica Organometꢀlica “Enrique Moles”
Unidad Asociada al CSIC, Universidad de Oviedo
Juliꢀn Claverꢂa 8, 33006 Oviedo (Spain)
Fax : (+34)985103450
E-mail: barluenga@uniovi.es
Scheme 1. The concept of the tandem catalytic hydroalkoxylation/Prins-
type cyclization reaction for the synthesis of bicyclic ethers. M=metal,
Nu=nucleophile.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200900856.
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FULL PAPER
a subsequent Prins-type cyclization[12] to finally give bicyclic
ethers in an apparently very simple way. By varying both
the structure of the alkynol derivative and the nucleophile,
the sequence would provide an excellent method for the
synthesis of structurally diverse collections of small mole-
cules. Detailed studies on this process are reported herein.
could be performed at room temperature (Table 1, en-
tries 3–5). Moreover, the catalyst loading could be decreased
to 1 mol% (complete conversion required 6 h; Table 1,
entry 4) or even to 0.5 mol% (complete conversion required
30 h; Table 1, entry 5); also, gold(I) compounds catalyzed
the reaction. However, some comments on the use of these
catalysts should be made: When 2 mol% of AuCl was used,
2a was formed, although the conversion was only 56% after
12 hours at 658C (55% yield of isolated 2a; Table 1,
entry 6). We did not observe any transformation by using
Results and Discussion
Initial experiments and selection of appropriate catalysts:
Initial attempts to promote the tandem sequence discussed
above were performed by using the model diallyl-substituted
alkynol 1a as the starting material and methanol as both the
solvent and nucleophile. First, we focused on finding the ap-
propriate catalyst, and so we treated alkynol 1a with several
metallic complexes. The most significant results are summar-
ized in Table 1.
[AuCl
2 mol% of [AuCl
ate the cationic gold(I) complex, we observed the exclusive
formation of product 2a after 7 hours at 658C (Table 1,
entry 8). Similar results were found by using the cationic
gold(I) complex generated from [AuClACTHNUTRGNEUNG(tht)] (tht=tetrahy-
drothiophene). In this case, the catalyst loading could be de-
creased to 1 mol% (Table 1, entry 9).
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
Next, we turned our attention to platinum complexes. The
reaction with the platinum(II) complex [PtACTHNURTGNENG(U cod)Cl2] (cod=
Table 1. Cycloisomerization reactions of the alkynol 1a: optimization of
4-cycloocta-1,5-diene) did not proceed at room temperature
(Table 1, entry 10). However, on warming to 658C for
12 hours it was possible to isolate the final product 2a in
95% yield (catalyst loading was 2 mol%; Table 1, entry 11).
Regarding the platinum(IV) complexes, we tried the reac-
tion with PtCl4 and found that this was an excellent catalyst
to perform the transformation of 1a into 2a (Table 1, en-
tries 12–15). The reaction proceeded slowly at room temper-
ature with 2 mol% of PtCl4, and 2a was isolated in only
66% yield after 3 hours (68% conversion; Table 1,
entry 12). However, the reaction was complete after 30 mi-
nutes at 658C using 2 mol% of PtCl4, and 2a was isolated in
96% yield (Table 1, entry 13). The amount of catalyst could
be decreased to 0.5 mol% (complete conversion required
2 h; Table 1, entry 14). By using only 0.1 mol% of PtCl4, the
reaction took 18 hours to go to completion (Table 1,
entry 15). Under these conditions, product 2a was isolated
in 95% yield as a single diasteresoisomer.
the catalyst.
Entry
MLn
x
Conditions[a]
[h]
Yield
[%][b]
AHCTUNGTRENGN[UN mol%]
1
2
AgOTf
Cu
5
5
2
1
0.5
2
2
2
1
2
2
2
2
0.5
0.1
2
658C
658C
RT
15
168
1
>95
>95
>95 (94)
>95
>95
56 (55)
0
>95 (95)
>95
(OTf)2
3
4
5
6
AuCl3
AuCl3
AuCl3
AuCl
RT
6
RT
30
658C
658C
658C
658C
RT
12[c]
7
A
R
24[d]
7
8
A
E
[e]
9
A
A
6
10
11
12
13
14
15
16
17
N
T
24[d]
12
0
N
658C
RT
>95 (95)
68 (66)
>95 (96)
>95
>95 (95)
>95
3[e]
0.5
2
658C
658C
658C
658C
658C
Finally, the process was attempted with palladium(II)
complexes as catalysts. The reaction worked well with
2 mol% of PdCl2, although it was slower (complete conver-
sion required 18 h at 658C) than those reactions performed
with platinum or gold catalysts (Table 1, entry 16). We did
18
18
2A
2
24[d]
0
[a] Unless otherwise stated, the time shown is that required to reach
>99% conversion. [b] The yield of product 2a as determined by GC; the
yield of the isolated spectroscopically pure product 2a is given in paren-
theses. [c] A conversion of 56% was determined by GC; 42% yield of 1a
recovered after column chromatography. [d] No conversion as deter-
mined by GC. [e] A conversion of 70% was determined by GC. L=
ligand, OTf=trifluoromethanesulfonate.
not observe any transformation by using [PdCl
the catalyst (Table 1, entry 17). From this extensive study, it
can be concluded that silver(I), copper(II), gold(III),
2ACHTUNGRTNE(NUNG PPh3)2] as
ACHTUNGTRENNUNG
gold(I), platinum(II), platinum(IV), and palladium(II) com-
pounds could be appropriate catalysts for our tandem pro-
cess. However, in general, we decided to use AuCl3, [PtCl2-
AHCTUNGTRENG(UNN cod)], or PtCl4 as catalysts in successive experiments due to
their higher activity and/or ease of handling (in some cases,
cationic gold(I) complexes were also considered).
Silver(I) and copper(II) triflate salts were proven to be ef-
fective catalysts for the tandem process (Table 1, entries 1
and 2). However, to obtain complete conversion of the start-
ing materials, high catalyst loading and long reaction times
were required. More effective were the gold catalysts. In
Mechanism of the reaction: To gain insight into the mecha-
nism of the reaction we performed labeling studies with
deuterated starting materials or solvents (Scheme 2). The re-
action of 1a in CD3OD in the presence of 2 mol% of [PtCl2-
fact, by using the goldACHTUNGTRENUNG(III) compound AuCl3, the reaction
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J. Barluenga et al.
believed to proceed through a chair-like transition state in
which the axial allyl moiety reacts to form the oxocarbeni-
um ion 7. Further nucleophilic trapping from an equatorial
trajectory by a molecule of methanol accounts for the for-
mation of 2a and the regeneration of the catalytic species
after a final proto-demetallation step.[14]
This rationalization is consistent with the configuration of
the stereogenic centers observed in 2a. Additional support
for this mechanistic proposal can be found in the previously
commented upon labeling experiments. Formation of deu-
terated compounds [D1]-2a and [D7]-2a clearly support a
Lewis acid-type activation of the starting alkyne, thus ruling
out any possible mechanism initiated by an insertion of the
Scheme 2. Labeling experiments for the catalytic transformation of 1a
and [D1]-1a.
À
À
metallic species into the terminal C H (or C D) bond of
the triple bond. Also, formation of the deuterated com-
pound [D7]-2a is in good agreement with the participation
of an oxocarbenium ion 6 as an intermediate. Thus, the
acidic hydrogen atoms in the a position to the oxocarbeni-
um group are deuterated by CD3OD prior to the cyclization
step.
ACHTUNGTRENNUNG(cod)] at 658C for 12 hours cleanly afforded the heptadeu-
terated compound [D7]-2a in 93% yield. Moreover, reaction
of the deuterated alkyne [D1]-1a in CH3OH under the same
conditions led to the formation of product [D1]-2a in 92%
yield.
All these experiments support a mechanism for the for-
mation of 2a based on a tandem sequence that involves an
intramolecular hydroalkoxylation reaction in the first place
followed by a Prins-type cyclization process (Scheme 3). The
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 3. In principle,
both Lewis and Brønsted acids could catalyze the hydroal-
koxylation and the Prins-type cyclization reactions. It should
be taken into account that traces of Brønsted acids could be
formed in the reaction media from the platinum or gold
complexes and these protic acids could be responsible for
both or at least one of the catalytic cycles proposed in
Scheme 3.[15] So, to shed light on this issue, alkynol 1a was
subjected to a range of reaction conditions with methanol as
the solvent. No reaction was observed in the absence of
platinum or gold complexes or by treatment of 1a with
Brønsted acids such as para-toluenesulfonic acid (p-TsOH)
and tetrafluoroboric acid, thus demonstrating the necessity
of the metallic complex at least for the hydroalkoxylation
reaction. Also, to eliminate the possibility of competing
Brønsted acid catalysis in the second catalytic cycle (i.e., the
Prins-type reaction), we performed control experiments
using a nonpoisoning base. Thus, when 1a was treated with
5 mol% of PtCl4 in a solution containing 2.5 mol% of the
strong phosphorine base 2-tert-butylimino-2-diethylamino-
1,3-dimethyl-perhydro-1,3,2-diazaphosphorine (BEMP) in
methanol, we observed the formation of the expected prod-
uct 2a after 1 h at room temperature. These results suggest
that residual Brønsted acids are not responsible because
these would be quenched by BEMP (at 2.5 mol%). So we
believe that the gold or platinum catalytic species are in-
volved in both the catalytic cycles proposed in Scheme 3.[16]
Scheme 3. Proposed mechanism for the formation of eight-membered
carbocycle 2a from alkynol 1a.
reaction is initiated by coordination of the platinum or gold
complex to the triple bond of the starting alkynol 1 to form
intermediate 3 according to the Dewar–Chatt–Duncanson
model.[13] Intramolecular addition of the hydroxy group to
the internal carbon atom of the triple bond generates 4. Pro-
todemetallation of the latter affords the exo-cyclic enol
ether 5 and regenerates the catalytic species. At this point,
the second part of the tandem sequence, the Prins-type cyc-
lization, is initiated. Thus, after an initial coordination of the
catalyst to the double bond of the enol ether, the oxonium
intermediate 6 is formed. The subsequent cyclization step is
Generalization of the reaction—variation of the alkynol and
the alcohol used as the nucleophile: Once we had found the
appropriate catalysts and conditions to perform the reaction,
we focus on the scope of this process. It is important to note
that, in principle, this reaction offers the possibility of ac-
cessing interesting bicyclic compounds with many points of
diversity in a very simple way (Scheme 4). Moreover, as the
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Regio- and Stereoselective Catalytic Cascade Reactions
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Table 3. Cycloisomerization reactions of heteroatom-containing alkynol
derivatives 1g–j in the presence of different alcohols.
Scheme 4. From simple alkynols to bicyclic compounds. Potential diversi-
ty points are highlighted.
Alkynol
X
Product
R
Yield [%][a]
1g
1g
1g
1h
1i
O
O
O
PhN
4-MeOC6H4N
TsN
2m
2n
2o
2p
2q
2r
iPr
Me
Pr
Me
Me
Me
93
reaction occurs with total regio- and diastereoselectivity, it
would be possible to synthesize enantiomerically pure prod-
ucts.
We began our study on the generality of the reaction by
using simple variations in the structure of the starting alky-
nol derivative and the alcohol used as the nucleophile. Dif-
ferent substituents at the carbon atom bearing the hydroxy
group were tolerated (Table 2). Additionally, a number of
95
91[b]
89
90
93
1j
[a] The yield of the isolated spectroscopically pure product 2. [b] Re-
action carried out with AuCl3 (2 mol%) as the catalyst at room tempera-
ture. Ts=para-toluenesulfonyl.
that similar results were observed by using the correspond-
ing platinum(II), goldACTHNUTRGNE(NUG III), and gold(I) complexes.
Table 2. Reaction of the alkynol derivatives 1a–f in the presence of dif-
ferent alcohols.[a]
Another interesting point for appendage variation is the
triple bond of the starting alkynol derivative. In all the ex-
amples shown so far, we have used alkynol derivatives with
a terminal triple bond as the starting materials. However,
the reaction also worked with internal triple bonds
(Table 4), and both aryl and alkyl groups at the triple bond
Alkynol
R1
MLn
[Pt(cod)Cl2]
AuCl3
[AuCl
[PtCl2A(cod)]
AuCl3
[PtCl2A(cod)]
[PtCl2A(cod)]
AuCl3
[PtCl2A(cod)]
Product
R
Yield [%][b]
1a
1a
1a
1b
1b
1c
1d
1d
1e
1e
1 f
allyl
allyl
allyl
Me
Me
Bu
iPr
iPr
tBu
tBu
H
G
2b
2c
2d
2e
2 f
2g
2h
2i
Et
Pr
92
94
80
94
96
92
92
88
90
91
88
Table 4. Cycloisomerization reactions of the alkynol derivatives 1k–o
containing an internal triple bond in the presence of different alcohols.
[c]
G
N
Bn
Me
Et
Me
Me
Et
Me
Et
Me
E
CHTUNGTRENNUNG
E
C
T
CHTUNGTRENNUNG
A
E
2j
2k
2l
AuCl3
PtCl4
Alkynol
R1
R2
X
Product
R
Yield [%][a]
1k
1l
1m
1n
1n
1o
Et
Ph
Me
Et
Pr
Pr
Ph
CH2
O
O
O
O
2s
2t
2u
2v
2w
2x
Me
Me
Me
Me
Et
81
89
91
89
93
87
[a] The reactions were performed at room temperature when AuCl3 was
used as the catalyst, whereas the reactions were performed at 65–808C
with all the other catalysts. [b] The yield of the isolated spectroscopically
pure product 2.
allyl
allyl
allyl
allyl
allyl
O
Me
[a] The yield of isolated spectroscopically pure product 2.
alcohols proved to be effective nucleophiles. All the cata-
lysts, that is, those based on platinum(II), platinum(IV),
gold
(III), and cationic gold(I), gave the corresponding bicy-
were appropriate substituents. We observed that for this
type of substrate the most suitable catalyst was PtCl4. So, in
general, these reactions were performed by warming a solu-
tion of alkynol 1 in the corresponding alcohol at 65–808C
(depending on the alcohol used as nucleophile) for 12 hours
and utilizing 2 mol% of PtCl4 as the catalyst.
clic compounds 2 in essentially the same yield. It is also im-
portant to note that in all cases only one diastereoisomer of
the final product was formed.
To increase the molecular diversity, a number of experi-
ments were attempted by using alkynol derivatives 1, which
contain a heteroatom in the chain that connects the hydroxy
functionality and the triple bond, as starting materials
(Table 3). We studied the effect of the presence of both
oxygen and nitrogen atoms. The reaction led to the expected
bicyclic compounds 2 in high yield and as single diastereo-
isomers (Table 3). The structure of compound 2r was veri-
fied by X-ray crystallographic analysis.[17] Although results
summarized in Table 3 correspond to those reactions per-
formed by using PtCl4 as the catalyst, it should be noted
Other oxygen-centered nucleophiles: At this point, we
turned our attention to the nucleophile and, in particular, to
the use of other oxygenated nucleophiles than alcohols.
Thus, we investigated the reaction with carboxylic acids as
the nucleophiles. These reactions were performed by mixing
alkynol 1a with 2 mol% of [PtCl2ACTHNUGTRNEUNG(cod)] in the correspond-
ing carboxylic acid as the solvent at 808C for 12 hours
(Scheme 5). Under these conditions, the ester derivatives
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J. Barluenga et al.
And finally, a Friedel–Crafts alkylation could be considered
for the introduction of carbon-centered nucleophiles
(Scheme 6).[20]
So, we heated a solution of alkynols 1 in acetonitrile and
1.5 equivalents of H2O in the presence of 2 mol% of PtCl4
to reflux for 6 h to introduce the nitrogen-centered nucleo-
philes. Under these conditions, amide derivatives 10 were
isolated in very high yield and as single diastereoisomers
(Table 5). Crystals of 10a were obtained from a pentane/di-
chloromethane mixture that were suitable for X-ray analysis,
thus confirming the proposed structure.[17] We also observed
that these reactions may also be carried out with 2 mol% of
AuCl3 as the catalyst.
Scheme 5. Carboxylic acids as nucleophiles: the catalytic synthesis of
ester derivatives 8a,b and further transformation into alcohol 9.
8a,b were isolated in high yield and as single diastereoiso-
mers. Furthermore, treatment of the propionic acid deriva-
tive 8b with potassium carbonate in methanol led to the for-
mation of the hydroxy-substituted eight-membered carbocy-
cle 9. This result is interesting because 9 is formally obtained
from a reaction in which H2O is used as the nucleophile. It
should be noted that we could not achieve the direct reac-
tion of alkynols 1 and water as the nucleophile under any of
the reaction conditions attempted. So, the alternative se-
quence shown in Scheme 5 seems an appropriate strategy to
obtain hydroxy-substituted derivatives such as 9.
Table 5. Catalytic synthesis of amide derivatives 10 using nitrogen-cen-
tered nucleophiles.
Alkynol
R1
R2
X
Product
Yield [%][a]
Nitrogen-centered, carbon-centered, and halogen nucleo-
philes: Having succeeded in the introduction of oxygen-cen-
tered nucleophiles and bearing in mind that the tandem hy-
droalkoxylation/Prins-type cyclization would formally pro-
vide a carbocationic intermediate, we thought that this car-
bocation could be trapped by other types of nucleophiles
(Scheme 6). For example, for the introduction of nitrogen-
centered nucleophiles we considered the possibility of a
Ritter-type reaction.[18] We also believed that halogenated
compounds could be obtained as a result of halide abstrac-
tion from a halocarbon atom by the intermediate cation.[19]
1a
1c
1g
1k
allyl
Bu
allyl
Et
H
H
H
Ph
CH2
CH2
O
10a
10b
10c
10d
86
84
89
87
CH2
[a] The isolated yield of the isolated spectroscopically pure product 10.
Next, we studied the possibility of introducing a halogen
atom into the molecule. The use of CH2Cl2 and CH2Br2 as
both the solvents and halogen sources resulted in the effi-
cient incorporation of chlorine and bromine atoms into the
reaction products. These reactions were performed with
2 mol% of PtCl4 as the catalyst to provide compounds 11 in
high yield as single diastereoisomers (Table 6).
Interestingly, when the reaction discussed above was car-
ried out with 2 mol% of [AuClACHTNUGRTENUNG(PPh3)]/AgOTf as the cata-
lyst in dichloromethane as the solvent, we did not observe
Table 6. Catalytic synthesis of halogenated derivatives 11.
Alkynol
R1
R2
X
Y
Product
Yield [%][a]
1a
1a
1b
1g
1k
1p
allyl
allyl
Me
allyl
Et
H
H
H
H
Ph
H
CH2
CH2
CH2
O
CH2
CH2
Cl
Br
Cl
Cl
Cl
Cl
11a
11b
11c
11d
11e
11 f
92
76[b]
90
78
83
85
Et
[a] The yield of the isolated spectroscopically pure product 11. [b] Trace
amounts of the corresponding chlorinated compound 11a were detected
in the crude product.
Scheme 6. Proposed reactions for the incorporation of nitrogen-, halo-
gen-, and carbon-centered nucleophiles.
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Regio- and Stereoselective Catalytic Cascade Reactions
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the incorporation of a chlorine atom into the final product;
instead, the elimination product 12 was isolated as a mixture
of two regioisomers (Scheme 7). Further catalytic hydroge-
nation of this mixture afforded 13 as a single isomer in 96%
Synthesis of enantiomerically pure products: a-Hydroxy
acids and a-amino acids are useful building blocks in organ-
ic synthesis and are common core structures for a number of
synthetically challenging and medicinally important agents.
In this context, we thought that our tandem catalytic reac-
tion could be applied to alkynols derived from lactic acid
and natural a-amino acids to obtain enantiomerically pure
compounds with potential utilities in pharmacological areas.
We then synthesized alkynol derivatives 15 and 17 from
(À)-ethyl d-lactate and several l-amino esters, respectively,
by using conventional organic transformations (Scheme 9).
Scheme 7. Catalytic synthesis of diene derivatives 12 and further transfor-
mation into bicyclic ether 13.
yield. Formally, this simple two-step sequence could be seen
as a tandem hydroalkoxylation/Prins-type cyclization reac-
tion in which a hydride ion acted as the nucleophile.
From the point of view of organic synthesis, a major chal-
lenge is the creation of new carbon–carbon bonds. So the
possibility of employing carbon-centered nucleophiles in our
reaction was an attractive goal. To this end, as previously
noted, we considered the tandem hydroalkoxylation/Prins-
type cyclization/Friedel–Crafts alkylation shown in
Scheme 6. These reactions were performed by treating alky-
nol 1a,g with 2 mol% of [AuClACHTNUGRTENUNG(PPh3)]/AgOTf in the pres-
ence of the corresponding aromatic compound (1.5 equiv-
alents) and with dichloromethane as the solvent (Scheme 8).
As shown, electron-rich aromatic compounds were appropri-
ate reagents to effect this reaction. Thus, compounds 14
were isolated in high yield as single diastereoisomers.
Scheme 9. Enantiopure bicycloACTHNUGRTENUNG[3.3.1]nonanes derived from d-lactate and
l-amino esters. Reagents and conditions: a) NaH, RCꢀCCH2Br; b)
H2C=CHCH2MgBr; c) PtCl4 (2 mol%) in MeOH, CH3CN/H2O, or 1,3,5-
trimethoxybenzene/CH2Cl2; d) TsCl, Et3N. See the Supporting Informa-
tion for details. The yields in parenthesis refer to the last step (c). Ts=
para-toluenesulfonyl.
Further treatment of these alkynol derivatives with 2 mol%
of PtCl4 in the presence of an appropriate nucleophile under
the optimized reaction conditions previously described led
to the formation of 16 or 18 in high yield and as single dia-
stereoisomers and enantiomers. The structures of 16b and
18b,d were verified by X-ray crystallographic analysis.[17]
Interestingly, we observed the opposite chiral induction
when starting from alkynol 15, derived from d-lactate, or
from alkynol 17, derived from l-amino acids. To justify this
fact, we need focus on the mechanism of the reaction and,
in particular, on the structure of the corresponding inter-
mediate 6 (Scheme 3 and Figure 1). Thus, for d-lactate-de-
rived product 16 the reaction should proceed through inter-
Scheme 8. Carbon-centered nucleophiles: the catalytic synthesis of bicy-
clic compounds 14.
Chem. Eur. J. 2009, 15, 11660 – 11667
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Figure 1. Proposed intermediates 6 that justify the stereochemistry ob-
served in 16–18.
mediate 6A (Figure 1). As shown, the methyl group is
placed in a pseudoequatorial position in this structure. How-
ever, to explain the formation of 18, derived from l-amino
acids, the reactions should proceed through intermediate 6B
in which the R group is placed in a pseudoaxial position
(Figure 1).[21]
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Conclusions
We have developed a new, highly efficient method for the
synthesis of complex bicyclic compounds from easily avail-
able alkynol derivatives. The reaction is based on a tandem
process that involves an intramolecular hydroalkoxylation of
a triple bond followed by a Prins-type cyclization. Although
several metallic complexes catalyzed this transformation,
those complexes derived from gold and platinum were the
most efficient. Simple variations on the structure of the
starting alkynol derivative or in the nature of the nucleo-
phile used allowed the synthesis of more than fifty new com-
pounds, including products in their enantiomerically pure
form. The [3.3.1]bicyclic systems obtained through this strat-
egy are natural-like structural motifs that might be of value
in the discovery of biologically active molecular agents. In
this context, the process described herein is well-suited for
drug-discovery programs, and the enantiomerically pure
products that are easily obtained from a-amino acids and
lactic acid are remarkable products.
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Acknowledgements
We gratefully acknowledge financial support from the MICINN
(CTQ2007-61048/BQU), PRINCAST (IB08-088). We also thank Dr
Angel L. Suꢀrez for his help in the X-ray structure determination.
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Regio- and Stereoselective Catalytic Cascade Reactions
FULL PAPER
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Received: April 1, 2009
Published online: September 16, 2009
Chem. Eur. J. 2009, 15, 11660 – 11667
ꢃ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11667