Gold-catalyzed direct cycloketalization of acetonide-tethered alkynes in the presence of water

Article abstract of DOI:10.1016/j.tet.2012.09.030

A methodology for the direct preparation of bridged acetals from acetonide-tethered alkynes under gold catalysis in the presence of water has been developed. The bicyclic ring structures bearing a bridged five-membered ring arise from the regioselective b

Full text of DOI:10.1016/j.tet.2012.09.030

Tetrahedron 68 (2012) 9391e9396
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Gold-catalyzed direct cycloketalization of acetonide-tethered alkynes in the
presence of water
,
b
,
a
Benito Alcaide a , Pedro Almendros , Rocío Carrascosa
*
*
a
ꢀ
Grupo de Lactamas y Heterociclos Bioactivos, Departamento de Química Organica I, Unidad Asociada al CSIC, Facultad de Química, Universidad Complutense de Madrid,
28040 Madrid, Spain
b
ꢀ
Instituto de Química Organica General, IQOG, Consejo Superior de Investigaciones Científicas, CSIC, Juan de la Cierva 3, 28006 Madrid, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 18 July 2012
Received in revised form 31 August 2012
Accepted 4 September 2012
Available online 11 September 2012
A methodology for the direct preparation of bridged acetals from acetonide-tethered alkynes under gold
catalysis in the presence of water has been developed. The bicyclic ring structures bearing a bridged five-
membered ring arise from the regioselective bis-oxycyclization by initial attack of the oxygen atom to the
internal alkyne carbon.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Acetals
Alkynes
Cyclization
Gold
Regioselectivity
1. Introduction
4-yl)methanol, from (S)-2-(2,2-dimethyl-1,3-dioxolan-4-yl)etha-
nol, or from 2-O-benzyl-D-threitol.
Over the course of the last decade, efforts aimed at maximizing
the total efficiency of a given organic transformation have been in-
creased.1 The use of gold salts has gained a lot of attention in the
recent times because of their powerful soft Lewis acidic nature.2 In
particular, the recently developed noble metal activation of alkynes
toward simultaneous attack by two contiguous oxygen nucleophiles
is an important CeO bond-forming reaction.3,4 However, these re-
ports involve the use of free hydroxy groups; being missed the direct
bis(oxycyclization) sequence of acetonide-tethered alkynes until we
merged into this field.5 In connection with our current research in-
terest in the preparation of biologically relevant heterocycles,6 we
wish to report now details of the direct cycloketalization of
acetonide-tethered alkynes to bridged bicyclic acetals, which is
carried out using gold catalysis in the presence of water.
Alkynyldioxolanes 1aeh were prepared as shown in Scheme 1.
Alkynyldioxolanes 1a and 1b were prepared from (S)-(þ)-1,2-
isopropylideneglycerol through O-propargylation and Sonoga-
shira coupling. Precursors 1ceh were prepared from (R)-2,3-O-
isopropylideneglyceraldehyde via metal-mediated carbonyl-
R
O
N
O
R1
R2
O
O
O
O
R
O
O
1
(+)-3a
(–)-3b
(–)-3c
(–)-3d
(+)-2a
R
R
R
R
= Bn, R2 = H
R = H
(+)-1a R = H
(+)-1b
1 = CO2Me, R2 = H
(–)-2b R = Ph
R = PMP
1 = CO2Me, R2 = Ph
1 = CO2Me, R2 = Thiophenyl
R
R
OBn
O
O
O
O
O
O
2. Results and discussion
(+)-2c R = H
(+)-1c R = H
Starting substrates, alkynyldioxolanes 1aeh, 2aee, and 3aed
(Fig. 1) required for our study were prepared from (R)-2,3-O-iso-
propylideneglyceraldehyde, from (S)-(2,2-dimethyl-1,3-dioxolan-
(+)-2d
R = Me
(+)-1d
R = D
(+)-2e R = Ph
(–)-1e R = Ph
(–)-1f R = 2-Pyridyl
(+)-1g
R =
Ph
(+)-1h R = Et
* Corresponding authors. Tel.: þ34 91 3944314; fax: þ34 91 3944103 (B.A.); tel.:
þ34 91 5618806; fax: þ34 91 5644853 (P.A.); e-mail addresses: alcaideb@qui-
m.ucm.es (B. Alcaide), Palmendros@iqog.csic.es (P. Almendros).
Fig. 1. Structures of cyclization precursors, alkynyldioxolanes 1aeh, 2aee, and 3aed.
PMP¼4-MeOC6H4.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.09.030

9392
B. Alcaide et al. / Tetrahedron 68 (2012) 9391e9396
allylation followed by O-propargylation, deuteration, Sonogashira
and CadioteChodkiewicz couplings, as appropriate.
breakthrough for metal-catalyzed alkyne-cycloketalization in
terms of cost-effectiveness. Initial experiments were carried out
using alkynyldioxolane 1a as a model substrate. To optimize the
reaction method, different parameters involved in the metal-
catalyzed reactions that could affect the formation of the desired
product were tested. Attempts of the cyclization reaction of 1a
using AgOTf, FeCl3, and [PtCl2(CH2]CH2)]2 catalysts failed. Nicely, it
was found that [AuClPPh3]/AgOTf along with a Brønsted acid (PTSA)
in CH2Cl2 was a competent catalytic system for this purpose (see
table).9,10 Performing the reaction at 80 ꢀC on a sealed tube accel-
erated the reaction. However, the conversion to the corresponding
tricyclic acetal 4a could not be satisfied in high yield. Solvent
screening demonstrated that dichloromethane was the best choice
in the reaction. The use of a more Lewis acidic gold salt (AuCl3) as
catalyst alone without PTSA was also tested. Thus, we treated
alkynic acetonide 1a with 5 mol % of AuCl3. However, acetal 4a was
obtained in a poor 25% yield. After identifying an appropriate cat-
alyst, we optimized other critical reaction parameters, such as the
addition of additives. In particular, the transformation was strongly
influenced by the presence of water. Gratifyingly, it was found that
alkynic acetonide 1a on exposure to the system [AuClPPh3]
(2.5 mol %)/AgOTf (2.5 mol %)/PTSA (10 mol %)/H2O (100 mol %) in
dichloromethane at 80 ꢀC on a sealed tube, directly afforded bi-
cyclic ketal 4a through a regio- and diastereoselective bis(oxycyc-
lization) (see Table 1). Probably, the presence of water favors the
hydrolysis of intermediate 10 in the mechanistic proposal of
Scheme 4. Taking into account that there are only a few gold-
catalyzed transformations, which tolerate the presence of water,11
there would be certain merit using water as an alternative
solvent for alkyne-cycloketalization.12 To test for conditions for the
reaction as a suspension in water, we try our optimized catalytic
system. Notably, substrate 1a is completely insoluble in aqueous
media. After some experimentation, we observed that the cycliza-
tion reaction did not proceed ‘on water’. Thus, the use of biphasic
water/dichloromethane mixtures was necessary in order to im-
prove the solubility of the substrates; being (4:1 water/dichloro-
methane) the best solvent system. The presence of a phase transfer
agent13 gave rise to a positive influence on the yield of bridged
O
O
ii)
OH
i)
PMP
O
O
O
O
O
O
(+)-1a
(S
)-(+)-1,2-isopropylideneglycerol
(100%)
(+)-1b
(53%)
D
O
O
O
(+)-1d (61%)
iv)
R
O
OH
O
CHO
ii)
Br
i)
O
O
O
O
iii)
O
O
O
O
(
R
)-2,3-
O
-isopropyli-
(
S
)-1-[(R)-2,2-dimethyl-1,3-dioxolan-4-
(–)-1e
R=Ph (59%)
(–)-1f
(+)-1c (57%)
v)
deneglyceraldehyde
yl]-2,2-dimethylbut-3-en-1-ol (52%)
R= 2-Py (64%)
vi)
vii)
Ph
O
Et
O
O
O
O
O
(+)-1g
(43%)
(+)-1h (36%)
Scheme 1. Reagents and conditions: (i) propargyl bromide, CH2Cl2/NaOH (aq 50%),
TBAI, RT, 24 h; (ii) 2 mol % CuI, 1 mol % Pd(PPh3)2Cl2, ArI, Et3N, acetonitrile, rt, 15 h; (iii)
In, THF/NH4Cl (aq satd), rt, 15 h; (iv) BuLi, D2O, THF, ꢁ78 ꢀC to rt; (v) NBS, AcOAg,
acetone; (vi) phenylacetylene, CuCl, NH2OH, EtNH2, CH2Cl2/MeOH, 0 ꢀC to rt; (vii) 1-
bromopent-2-yne, CH2Cl2/NaOH (aq 50%), TBAI, rt, 24 h.
Alkynyldioxolanes 2aee were prepared as shown in Scheme 2.
Alkynyldioxolanes 2a and 2b were prepared from (4S)-(þ)-4-(2-
hydroxyethyl)-2,2-dimethyl-1,3-dioxolane
through
O-prop-
argylation. Precursors 2cee were prepared from 2-O-benzyl-D-
threitol7 via O-isopropylidenation8 followed by O-propargylation
and Sonogashira coupling.
Table 1
Selective direct bis(oxycyclization) reaction of acetonide-tethered alkyne 1a under
modified metal-catalyzed conditionsa
O
metal catalyst, additive
O
O
O
O
O
Scheme 2. Reagents and conditions: (i) propargyl bromide or (3-bromoprop-1-ynyl)
benzene, CH2Cl2/NaOH (aq 50%), TBAI, rt, 24 h; In, THF/NH4Cl (aq satd), rt, 15 h; (ii)
10 mol % pyridinium p-toluenesulfonate, 2,2-dimethoxypropane, rt, 2 h; (iii) propargyl
bromide or 1-bromobut-2-yne, NaH, TBAI, THF, rt; (iv) 2 mol % CuI, 1 mol %
Pd(PPh3)2Cl2, ArI, Et3N, acetonitrile, rt, 15 h. TBAI¼tetrabutylammonium iodide.
acid (10 mol%)
solvent, temperature
(–)-4a
(+)-1a
Catalyst (mol %)
Additive
(mol %)
TDMPP (5) 24
t (h) Acid
T
Solvent
DCM
Yield
(%)
(ꢀC)
As shown in Scheme 3, alkynyldioxolanes 3aed were prepared
from (R)-2,3-O-isopropylideneglyceraldehyde through reductive
amination followed by protection and Sonogashira coupling, as
appropriate.
[PtCl2(CH2]CH2)]2
(2.5)
AgOTf (5)
FeCl3 (10)
AuCl3 (5)
d
20
d
d
d
d
d
24
24
24
24
3
d
d
20
20
DCM
DCM
DCM
DCM
DCM
DCM
THF
DCE
Toluene 76
4H2O:
1DCM
DCM
db
d
PTSA 80
PTSA 20
25
45
75
50
64
90
[AuClPPh3]/AgOTf (2.5)
[AuClPPh3]/AgOTf (2.5) H2O (100)
[AuClPPh3]/AgOTf (2.5) H2O (100)
[AuClPPh3]/AgOTf (2.5) H2O (100)
[AuClPPh3]/AgOTf (2.5) H2O (100)
[AuClPPh3]/AgOTf (2.5) H2O (100)
[AuClPPh3]/AgOTf (2.5) TBAI (10)
d
80
48
4
3
5
48
FeCl3 80
PTSA 80
PTSA 80
PTSA 80
PTSA 80
90
Scheme 3. Reagents and conditions: (i) propargyl amine, MgSO4, rt, 15 h; (ii) NaBH4,
methanol, 0 ꢀC, 30 min; (iii) benzylbromide, K2CO3, acetonitrile, rt; (iv) methyl chlor-
oformate, Et3N, CH2Cl2, rt, 2 h; (v) 2 mol % CuI, 1 mol % Pd(PPh3)2Cl2, ArI, Et3N, aceto-
nitrile, rt, 15 h.
[AuClPPh3]/AgOTf (2.5) H2O (100)
3
PTSA 80
100
a
Yield of pure, isolated product with correct analytical and spectral data.
PTSA¼p-toluenesulfonic
acid.
TDMPP¼tris(2,6-dimethoxyphenyl)phosphine.
DCM¼dichloromethane.
THF¼tetrahydrofuran.
DCE¼1,2-dichloroethane.
TBAI¼tetrabutylammonium iodide.
b
Using directly a dioxolane ring instead of the deprotected 1,2-
diol moiety as the starting material, would be a significant
Taking into account this result, AgOTf cannot be considered as a co-catalyst
because its action is restricted to form the cationic gold species by anion exchange.7

B. Alcaide et al. / Tetrahedron 68 (2012) 9391e9396
9393
acetal 4a.14 The reaction time has a crucial role in the amount of the
product obtained: the longer the reaction time, the better the yield,
with a best result of 90% at 48 h, because a short reaction time of 2 h
leads to a 20% yield.
2.5 mol% [AuClPPh3], 2.5 mol% AgOTf
10 mol% PTSA, sealed tube, 80 o
C
R
O
CH2Cl2
i) 100 mol% H2O, 3 h
ii) H2O:CH2Cl2 (4:1), 10 mol% TBAI, 48 h
O
O
O
R
O
O
(–)-4a R = H [100% for i); 90% for ii)]
(+)-1a
R = H
(–)-4b
R = PMP [73% for i); 69% for ii)]
(+)-1b R = PMP
R
2.5 mol% [AuClPPh3], 2.5 mol% AgOTf
10 mol% PTSA, sealed tube, 80 o
CH2Cl2
O
O
R
Et
O
C
Scheme 5. Preparation of 3,8,9-trioxabicyclo[4.2.1]nonanes 6. PMP¼4-MeOC6H4.
PTSA¼p-toluenesulfonic acid. TBAI¼tetrabutylammonium iodide.
O
O
O
+
O
O
O
i) 100 mol% H2O, 3 h
ii) H2O:CH2Cl2 (4:1), 10 mol% TBAI, 48 h
were obtained as exclusive reaction products, except for 3c. Al-
though substitution at the final position of the aminoalkyne had
little effect upon the regioselectivity of the reaction, alkynyldiox-
olane 7c underwent cycloketalization reaction to afford a mixture
of proximal and distal adducts 7c and 8c.
(+)-1c R = H
(+)-1d R = D
(–)-4c R = H [79% for i); 69% for ii)]
(–)-4d R = D [76% for i); 66% for ii)]
(–)-4e R = Ph [63% for i); 60% for ii)]
(+)-4f R = 2-Py [65% for i); 58% for ii)]
(+)-4g R =
(–)-1e
R = Ph
(–)-1f R = 2-Py
(+)-1g R =
Ph
Ph [52% for i); 40% for ii)]
(–)-5h
(–)-4h R = Et [34% for i);
(+)-1h
[66% for
i); 33% for ii)]
R = Et
+
22% for ii)]
Scheme 4. Preparation of 3,6,8-trioxabicyclo[3.2.1]octanes 4. PMP¼4-MeOC6H4.
PTSA¼p-toluenesulfonic acid. TBAI¼tetrabutylammonium iodide.
Having established the optimal reaction conditions, we explored
the scope of the methodology by subjecting a range of (prop-2-
ynyloxy)methyl-tethered dioxolanes 1beh to direct alkyne-
cycloketalization and the results are shown in Scheme 4. In both
cases (addition of 1 equiv of water as well as the presence of large
amount of water), the crude reaction mixtures are extremely clean
and the acetals are the only products detected. Tolerance toward
a variety of substituents (aliphatic, aromatic, and alkynyl groups)
on the acetylenic end was demonstrated by obtaining the corre-
sponding enantiopure bridged acetals 4 in good yields. Except for
ethyl-substituted alkynyldioxolane 1h, bicyclic ketals 4 were ob-
tained as single regio- and diastereomers through a 6-exo/5-exo
bis-oxycyclization by initial attack of the oxygen atom to the in-
ternal alkyne carbon. The exposure of ethyl-substituted alkyne 1h
to these reactions conditions afforded the 7-endo/5-exo bis-
oxycyclization bridged acetal 5h as major adduct, being the corre-
sponding 6-exo/5-exo adduct 4h the minor component. From these
experiments, it can be concluded that this catalytic system in the
presence of water enables regioselective control of the intra-
molecular ketalization reaction between the dioxolane unit and
a range of alkynes separated by three atoms. Besides, the method
using 1 equiv of water is superior to the method using water as
main solvent, in terms of yields and reaction time.
We further examined the scope of this methodology by in-
vestigating (prop-2-ynyloxy)ethyl-tethered dioxolanes 2aee,
alkynyldioxolane substrates with a four-atom chain at the junction
between the acetonide group and the alkyne. We were pleased to
observe that these modifications had little impact on the regio-
chemical control of the reaction (total regioselectivity was ob-
served in this series). Thus, the increase of the distance between the
reactive moieties in one atom favored the 7-exo/5-exo bis-
oxycyclization of the acetonide group toward the internal alkyne
carbon, affording proximal adducts 6 (Scheme 5).
Scheme 6. Preparation of 6,8-dioxa-3-azabicyclo[3.2.1]octanes 7. Thf¼2-thiophenyl.
PTSA¼p-toluenesulfonic acid. TBAI¼tetrabutylammonium iodide.
Our proposed mechanism is shown in Scheme 7. Initially, one of
the oxygen atoms of the alkynyldioxolanes 1e3 attacks through
(6þn)-exo alkoxyauration the gold-activated alkyne 9 to form
a vinylegold complex 10, which reacts with water through aceto-
nide hydrolysis and a deauration process, to give intermediate 11
(right circle) and releasing the gold catalyst. The reaction does not
stop at this stage; instead methylenic oxacycles 11 can be further
cyclized to give the functionalized bridged acetals 4e6 (left circle).
The second catalytic cycle starts with the coordination of the alkene
group by the gold salt, on forming the p-complex 12, which after 5-
exo cyclization would form the ate complex 13. Deauration linked
to proton transfer liberates adducts 4e6 with concomitant re-
generation of the gold catalyst, closing the second catalytic cycle
(Scheme 7). Because we had never isolated 11, it is also possible to
think in a Brønsted acid activation of the transient methylenic
Aza-analogues of bridged acetals 4e6 have been recently
identified as inhibitors of drug-resistant Candida albicans strains.15
Thus, the replacement of the cycloether oxygen for a nitrogen atom
was accomplished next. Similar trends to the oxa series were ob-
served under the same gold-catalyzed conditions in the presence of
water. Cyclization of aminoalkynes 3aed possessing a chiral diox-
olane ring results in the regio- and stereoselective formation of 6,8-
dioxa-3-azabicyclo[3.2.1]octanes 7 (Scheme 6). Bicyclic acetals 7
Scheme 7. A conceivable mechanistic explanation for the gold-catalyzed bis(oxycyc-
lization) of alkynyldioxolanes 1e3.

9394
B. Alcaide et al. / Tetrahedron 68 (2012) 9391e9396
intermediate 11. However, the successful gold-catalyzed cyclo-
ketalization reaction of alkynylacetonides in the absence of
Brønsted acid additive, may discard this assumption. With the aim
of trapping the organometal intermediate to confirm the mecha-
nism of this reaction, we performed deuterium labeling studies
with deuterium oxide. When the gold-catalyzed alkyne cyclo-
ketalization reaction of substrate 1e was carried out in presence of
D2O (4 heavy water/1 dichloromethane), adduct 4e with additional
deuterium incorporation (50% D) at the two protons of the benzylic
carbon was achieved (Scheme 8). The fact that the gold-catalyzed
conversion of alkyne 1e into bridged acetal 4e in the presence of
D2O partially afforded double deuterated [D]-4e, suggests that
deuterolysis of the carbonegold bonds in species 10 and 13 has
occurred.
cool to room temperature and filtered through a pack of Celite. The
filtrate was extracted with dichloromethane (3ꢂ5 mL), and the
combined extracts were washed twice with brine. The organic layer
was dried (MgSO4) and concentrated under reduced pressure.
Chromatography of the residue gave analytically pure adducts.
Spectroscopic and analytical data for pure forms of 4, 5, 6, and 7
follow.16
4.3. Method B. General procedure for the gold-catalyzed
bis(heterocyclization) reaction of alkynyldioxolanes 1, 2, and 3
using water as main solvent. Preparation of bridged acetals 4,
5, 6, and 7
[AuClPPh3] (0.0093 mmol), AgOTf (0.0093 mmol), p-toluene-
sulfonic acid (0.037 mmol), and tetrabutylammonium iodide
(0.037 mmol) were sequentially added to a stirred solution of the
corresponding alkynyldioxolane 1 (0.37 mmol) in a biphasic water
(4 mL)/dichloromethane (1 mL) mixture. The resulting mixture was
heated in a sealed tube at 80 ꢀC for 48 h. The reaction mixture was
allowed to cool to room temperature and filtered through a pack of
Celite.Thefiltratewasextractedwithdichloromethane(3ꢂ5 mL), and
the combined extracts were washed twice with brine. The organic
layer was dried (MgSO4) and concentrated under reduced pressure.
Chromatography of the residue gave analytically pure adducts.
Spectroscopicandanalyticaldataforpureformsof4, 5, 6, and7follow.
Scheme 8. Gold-catalyzed bis(oxycyclization) of alkynyldioxolane 1e in a heavy water
medium.
3. Conclusions
4.3.1. Bicyclic acetal (ꢁ)-4a. From 129 mg (0.76 mmol) of alky-
nyldioxolane (þ)-1a, and after chromatography of the residue using
petroleum ether/diethyl ether (3:1) as eluent gave the ketal (ꢁ)-4a
[method A: 99 mg, 100%; method B: 89 mg, 90%] as a colorless oil;
In conclusion, we have developed a convenient methodology for
the gold-catalyzed direct synthesis of bridged bicyclic acetals from
alkynyldioxolanes. The presence of water was beneficial for the
transformation. The method using 1 equiv of water is superior to
the method using water as main solvent, in terms of yields and
reaction time. A conceivable mechanism for the achievement of
bridged acetals may imply a regioselective bis-oxycyclization by
initial attack of the oxygen atom of the dioxolane moiety to the
internal alkyne carbon.
[a
]
D ꢁ0.5 (c 10.0, CHCl3); 1H NMR (300 MHz, CDCl3, 25 ꢀC):
¼4.42
d
(m, 1H), 4.23 (d, J¼6.6 Hz, 1H), 3.87 (m, 2H), 3.60 (dd, J¼11.4, 1.3 Hz,
1H), 3.54 and 3.49 (d, J¼11.1 Hz, each 1H), 1.36 (s, 3H); 13C NMR
(75 MHz, CDCl3, 25 ꢀC):
d
¼104.9, 74.6, 72.6, 68.5, 67.9, 19.3; IR
(CHCl3):
n
¼2924, 1101, 693 cmꢁ1; HRMS (ES): calcd for C6H11O3
[MþH]þ: 131.0708; found: 131.0705.
4.3.2. Bicyclic acetal (ꢁ)-4d. From 60 mg (0.25 mmol) of alky-
nyldioxolane (þ)-1c, and after chromatography of the residue using
hexanes/ethyl acetate (7:1) as eluent gave the ketal (ꢁ)-4d [method
4. Experimental section
4.1. General information
A: 38 mg, 76%; method B: 33 mg, 66%] as a yellow oil; [
a
]
D ꢁ0.6 (c
1
2.5, CHCl3); H NMR (300 MHz, CDCl3, 25 ꢀC):
d
¼5.96 (dd, J¼17.7,
1H NMR and 13C NMR spectra were recorded on a Bruker Avance
AVIII-700 with cryoprobe, Bruker AMX-500, Bruker Avance-300,
Varian VRX-300S or Bruker AC-200. NMR spectra were recorded
in CDCl3 solutions, except otherwise stated. Chemical shifts are
given in parts per million relative to TMS (1H, 0.0 ppm), or CDCl3
11.0 Hz, 1H), 5.00 (m, 2H), 4.38 (m, 2H), 3.73 (dd, J¼7.0, 5.7 Hz, 1H),
3.62 and 3.56 (d, J¼11.0 Hz, each 1H), 3.53 (s, 1H), 1.33 (t, 2H), 1.07
13
and 1.06 (s, each 3H); C NMR (75 MHz, CDCl3, 25 ꢀC):
d¼144.3,
112.3, 104.3, 84.3, 75.6, 74.2, 66.4, 38.8, 24.7, 23.8, 18.6 (t, J¼19.6 Hz,
CH2D); IR (CHCl3):
n
¼1094, 653 cmꢁ1; HRMS (ES): calcd for
(
13C, 77.0 ppm). Low and high-resolution mass spectra were taken
C11H18DO3 [MþH]þ: 200.1396; found: 200.1391.
on an AGILENT 6520 Accurate-Mass QTOF LC/MS spectrometer
using the electronic impact (EI) or electrospray modes (ES) unless
otherwise stated. IR spectra were recorded on a Bruker Tensor 27
4.3.3. Bicyclic acetal (þ)-4f. From 55 mg (0.17 mmol) of alky-
nyldioxolane (ꢁ)-1f, and after chromatography of the residue using
hexanes/ethyl acetate (2:1) as eluent gave the ketal (þ)-4f [method
spectrometer. Specific rotation [a]
is given in 10ꢁ1 deg cm2 gꢁ1 at
D
20 ꢀC, and the concentration (c) is expressed in gram per 100 mL.
All commercially available compounds were used without further
purification.
A: 30 mg, 65%; method B: 27 mg, 58%] as a colorless oil; [
a
]
D þ0.3 (c
1
1.8, CHCl3); H NMR (300 MHz, CDCl3, 25 ꢀC):
d¼8.54 (d, J¼3.8 Hz,
1H), 7.62 (td, J¼7.6, 0.4 Hz, 1H), 7.34 (d, J¼7.6 Hz, 1H), 7.16 (m, 1H),
5.94 (dd, J¼17.7, 11.0 Hz, 1H), 4.97 (m, 2H), 4.40 (m, 2H), 3.68 (m,
1H), 3.71 and 3.63 (d, J¼11.1 Hz, each 1H), 3.52 (s, 1H), 3.22 and 3.17
(d, J¼14.0 Hz, each 1H), 1.04 and 1.03 (s, each 3H); 13C NMR
4.2. Method A. General procedure for the gold-catalyzed
bis(heterocyclization) reaction of alkynyldioxolanes 1, 2, and 3
using 1 equiv of water. Preparation of bridged acetals 4, 5, 6,
and 7
(75 MHz, CDCl3, 25 ꢀC):
d
¼155.6, 148.9, 144.2, 136.3, 124.9, 121.8,
112.3, 105.0, 84.3, 75.7, 73.2, 66.5, 42.2, 38.9, 24.7, 23.8; IR (CHCl3):
n
¼1179, 1045 cmꢁ1; HRMS (ES): calcd for C16H22NO3 [MþH]þ:
[AuClPPh3] (0.0093 mmol), AgOTf (0.0093 mmol), and p-tolue-
nesulfonic acid (0.037 mmol) were sequentially added to a stirred
solution of the corresponding alkynyldioxolane 1 (0.37 mmol) in
dichloromethane (0.37 mL). The resulting mixture was heated in
a sealed tube at 80 ꢀC for 3 h. The reaction mixture was allowed to
276.1600; found: 276.1603.
4.3.4. Bicyclic acetal (þ)-6a. From 151 mg (0.82 mmol) of alky-
nyldioxolane (þ)-2a, and after chromatography of the residue using
petroleum ether/diethyl ether (2:1) as eluent gave the ketal (þ)-6a

B. Alcaide et al. / Tetrahedron 68 (2012) 9391e9396
9395
(d) Alcaide, B.; Almendros, P.; Alonso, J. M. Org. Biomol. Chem. 2011, 9, 4405; (e)
Hashmi, A. S. K. Angew. Chem., Int. Ed. 2010, 49, 5232; (f) Chem. Rev.; Lipshutz, B.,
Yamamoto, Y., Eds.; ACS: New York, NY, 2008; Vol. 108; (g) Chem. Soc. Rev.;
Hutchings, G. J., Brust, M., Schmidbaur, H., Eds.; RSC: Cambridge, 2008; Vol. 37;
(h) Bongers, N.; Krause, N. Angew. Chem., Int. Ed. 2008, 47, 2178; (i) Hashmi, A. S.
K.; Hutchings, G. J. Angew. Chem., Int. Ed. 2006, 45, 7896; (j) Muzart, J. Tetrahedron
2008, 6, 5815; (k) Hashmi, A. S. K. Chem. Rev. 2007, 107, 3180; (l) Zhang, L.; Sun, J.;
Kozmin, S. A. Adv. Synth. Catal. 2006, 348, 2271.
[method A: 66 mg, 56%; method B: 53 mg, 45%] as a colorless oil;
[
a]
D ꢁ0.01 (c 2.4, CHCl3); 1H NMR (300 MHz, CDCl3, 25 ꢀC):
¼4.60
d
(td, J¼6.9, 2.9 Hz, 1H), 4.11 (t, J¼7.0 Hz, 1H), 4.04 and 3.69 (ddd,
J¼12.4, 6.1, 3.1 Hz, each 1H), 3.98 (dd, J¼6.9, 2.9 Hz, 1H), 3.78 and
3.39 (d, J¼12.4 Hz, each 1H), 2.13 (m, 1H), 1.87 (dddd, J¼10.2, 6.1,
13
0.9 Hz, 1H), 1.35 (s, 3H); C NMR (75 MHz, CDCl3, 25 ꢀC):
d
¼110.6,
79.0, 74.2, 73.1, 68.1, 36.7, 21.5; IR (CHCl3):
n
¼1190 cmꢁ1; HRMS
3.
For the gold-catalyzed access to bicyclic ketalsˇ from terminal alkyne diols, see:
(ES): calcd for C7H13O3 [MþH]þ: 145.0865; found: 145.0868.
(a) Antoniotti, S.; Genin, E.; Michelet, V.; Genet, J.-P. J. Am. Chem. Soc. 2005, 127,
ꢀ
9976; For the platinum-catalyzed synthesis of bicyclic ketals, see: (b) Dieguez-
ꢀ
Vazquez, A.; Tzschucke, C. C.; Lam, W. Y.; Ley, S. V. Angew. Chem., Int. Ed. 2008,
4.3.5. Bicyclic acetal (ꢁ)-7b. From 56 mg (0.25 mmol) of alky-
nyldioxolane (ꢁ)-3b, and after chromatography of the residue using
hexanes/ethyl acetate (1:1) as eluent gave the ketal (ꢁ)-7b [method
47, 209; For the iridium-catalyzed access to bicyclic ketals from alkyne diols,
see: (c) Benedetti, E.; Simonneau, A.; Hours, A.; Amouri, H.; Penoni, A.; Palm-
isano, G.; Malacria, M.; Goddard, J.-P.; Fensterbank, L. Adv. Synth. Catal. 2011,
353, 1908.
A: 37 mg, 80%; method B: 34 mg, 73%] as a colorless oil; [
a
]D ꢁ0.1 (c
4. For the gold-catalyzed access to tricyclic cage-like ketals from diyne-diols and
1
1.4 in CHCl3); H NMR (300 MHz, CDCl3, 25 ꢀC):
d
¼4.46 (m, 1H),
€
€
external nucleophiles, see: (a) Hashmi, A. S. K.; Buhrle, M.; Wolfle, M.; Rudolph,
M.; Wieteck, M.; Rominger, F.; Frey, W. Chem.dEur. J. 2010, 16, 9846; For the
gold-catalyzed access to monocyclic ketals from alkynes and diols, see: (b)
3.85 (m, 3H), 3.77 and 2.92 (d, J¼5.6 Hz, 1H), 3.69 (s, 3H), 2.92 (d,
13
J¼12.8 Hz, 1H), 1.44 (s, 3H); C NMR (75 MHz, CDCl3, 25 ꢀC):
ꢀ
Corma, A.; Ruiz, V. R.; Leyva-Perez, A.; Sabater, M. J. Adv. Synth. Catal. 2010, 352,
1701.
d
¼159.5, 107.0, 75.9, 71.2, 55.6, 54.9, 49.8, 24.1; IR (CHCl3):
5. For
a preliminary communication of part of this work, see: Alcaide, B.;
n
¼1744 cmꢁ1; HRMS (ES): calcd for C8H14NO4 [MþH]þ: 188.0923;
Almendros, P.; Carrascosa, R.; Torres, M. R. Adv. Synth. Catal. 2010, 352, 1277.
found: 188.0924.
ꢀ
6. (a) Alcaide, B.; Almendros, P.; Alonso, J. M.; Fernandez, I. Chem. Commun. 2012,
ꢀ
ꢀ
6604; (b) Alcaide, B.; Almendros, P.; Aragoncillo, C.; Gomez-Campillos, G.; Arno,
M.; Domingo, L. R. ChemPlusChem 2012, 77, 563; (c) Alcaide, B.; Almendros, P.;
Luna, A.; Gomez-Campillos, G.; Torres, M. R. J. Org. Chem. 2012, 77, 3549; (d)
4.4. Procedure for the gold-catalyzed cyclization of alky-
nyldioxolane (L)-1e in a heavy water medium. Preparation of
acetal (L)-[D]-4e
ꢀ
Alcaide, B.; Almendros, P.; Carrascosa, R. Chem.dEur. J. 2011, 17, 4968; (e) Al-
ꢀ
caide, B.; Almendros, P.; Quiros, M. T. Adv. Synth. Catal. 2011, 353, 585; (f) Al-
caide, B.; Almendros, P.; Carrascosa, R.; Martínez del Campo, T. Chem.dEur. J.
2010, 15, 13243.
[AuClPPh3] (0.0065 mmol), AgOTf (0.0065 mmol), p-toluene-
sulfonic acid (0.025 mmol), and tetrabutylammonium iodide
(0.025 mmol) were sequentially added to a stirred solution of the
alkynyldioxolane (ꢁ)-1e (82 mg, 0.26 mmol) in a biphasic water
(0.4 mL)/dichloromethane (0.1 mL) mixture. The resulting mixture
was heated in a sealed tube at 80 ꢀC for 48 h. The reaction mixture
was allowed to cool to room temperature and filtered through
a pack of Celite. The filtrate was extracted with dichloromethane
(3ꢂ2 mL), and the combined extracts were washed twice with
brine. The organic layer was dried (MgSO4) and concentrated under
reduced pressure. Chromatography of the residue eluting with
hexanes/ethyl acetate (10:1) gave 41 mg (57%) of analytically pure
7. Steuer, B.; Lieberknecht, W. A.; Jager, V.; Bullock, J. P.; Hegedus, L. S. Org. Synth.
1996, 74, 1.
8. Hale, K. J.; Manaviazar, S.; George, J. H.; Walters, M. A.; Dalby, S. M. Org. Lett.
2009, 11, 733.
9. After control experiments it was demonstrated that the silver salt alone does
not catalyze the reaction of interest. Thus, it is believed that the role of the
silver salt just consists in the activation of the precatalyst: (a) Gaillard, S.;
ꢀ
Bosson, J.; Ramon, R. S.; Nun, P.; Slawin, A. M. Z.; Nolan, S. P. Chem.dEur. J. 2010,
16, 13729; However, despite proving that the silver activators themselves are
unreactive, there are examples of gold(I)-catalyzed reactions where Ag(I) salts
effected either activity or selectivity: (b) Tarselli, M. A.; Chianese, A. R.; Lee, S. J.;
ꢀ
Gagne, M. R. Angew. Chem., Int. Ed. 2007, 46, 6670; (c) Wang, D.; Cai, R.; Sharma,
S.; Jirak, J.; Thummanapelli, S. K.; Akhmedov, N. G.; Zhang, H.; Liu, X.; Petersen,
J. L.; Shi, X. J. Am. Chem. Soc. 2012, 134, 9012.
10. The reaction of alkynyldioxolane 1a in aqueous medium under gold catalysis in
the absence of acid additive (PTSA) proceeded to afford the corresponding
acetal 2a in just a slightly lower yield. For a seminal review on gold and pro-
tons, see: (a) Hashmi, A. S. K. Catal. Today 2007, 122, 211; For a selected report
on gold and protons, see: (b) Hashmi, A. S. K.; Schwarz, L.; Rubenbauer, P.;
Blanco, M. C. Adv. Synth. Catal. 2006, 348, 705.
adduct (ꢁ)-[D]-4e as a colorless oil; [
a
]
ꢁ0.4 (c 1.0, CHCl3); 1H
D
NMR (300 MHz, CDCl3, 25 ꢀC):
d
¼7.27 (m, 5H), 5.94 (dd, J¼17.6,
10.8 Hz, 1H), 4.98 (m, 2H), 4.40 (m, 2H), 3.69 (dd, J¼7.0, 5.6 Hz, 1H),
3.61 and 3.54 (d, J¼11.0 Hz, each 1H), 3.51 (s, 1H), 3.02 and 2.92 (d,
J¼14.2 Hz, each 1H), 1.05 and 1.04 (s, each 3H); 13C NMR (75 MHz,
11. (a) Minkler, S. R. K.; Lipshutz, B. H.; Krause, N. Angew. Chem., Int. Ed. 2011, 50,
7820; (b) Wang, Z. J.; Brown, C. J.; Bergman, R. G.; Raymond, K. N.; Toste, F. D. J.
Am. Chem. Soc. 2011, 133, 7358; (c) Poonoth, M.; Krause, N. J. Org. Chem. 2011, 76,
1934; (d) Yang, C. Y.; Lin, M. S.; Liao, H. H.; Liu, R. S. Chem.dEur. J. 2010, 16, 2696;
(e) Winter, C.; Krause, N. Green Chem. 2009, 11, 1309; (f) Ye, D.; Zhang, X.; Zhou,
Y.; Zhang, D.; Zhang, L.; Wang, H.; Jiang, H.; Liu, H. Adv. Synth. Catal. 2009, 351,
2770; (g) Marion, N.; Ramon, R. S.; Nolan, S. P. J. Am. Chem. Soc. 2009, 131, 448;
(h) Oh, C. H.; Karmakar, S. J. Org. Chem. 2009, 74, 370; (i) Cuenca, A. B.; Mancha,
CDCl3, 25 ꢀC):
d
¼144.5, 130.4, 128.4, 127.0, 112.6, 84.6, 77.5, 75.9,
73.4, 66.7, 40.1, 39.1, 25.0, 24.0; IR (CHCl3):
n
¼1184 cmꢁ1; HRMS
(ES): calcd for C17H22 DO3 [MþH]þ: 276.1709; found: 276.1705.
Acknowledgements
ꢀ
G.; Asensio, G.; Medio-Simon, M. Chem.dEur. J. 2008, 14, 1518; (j) Yang, C. Y.;
Lin, G. Y.; Liao, H. Y.; Datta, S.; Liu, R. S. J. Org. Chem. 2008, 73, 4907; (k) Zhang,
C.; Cui, D. M.; Yao, L. Y.; Wang, B. S.; Hu, Y. Z.; Hayashi, T. J. Org. Chem. 2008, 73,
7811; (l) Tang, J. M.; Liu, T. A.; Liu, Rˇ . S. J. Org. Chem. 2008, 73, 8479; (m) Genin,
E.; Leseurre, L.; Toullec, Y. P.; Genet, J.-P.; Michelet, V. Synlett 2007, 1780; (n)
Jung, H. H.; Floreancig, P. E. J. Org. Chem. 2007, 72, 7359; (o) Yan, B.; Liu, Y. Org.
Lett. 2007, 9, 4323; (p) Zhou, C. Y.; Chan, P. W. H.; Che, C. M. Org. Lett. 2006, 8,
325; (q) Casado, R.; Contel, M.; Laguna, M.; Romero, P.; Sanz, S. J. Am. Chem. Soc.
2003, 125, 11925; (r) Wei, C.; Li, C. J. J. Am. Chem. Soc. 2003, 125, 9584; (s)
Mizushima, E.; Sato, K.; Hayashi, T.; Tanaka, M. Angew. Chem., Int. Ed. 2002, 41,
4563.
Support for this work by the DGI-MICINN (Project CTQ2009-
ꢀ
09318) and Comunidad Autonoma de Madrid (Project S2009/
PPQ-1752) is gratefully acknowledged. R.C. thanks MEC for a pre-
doctoral grant.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2012.09.030.
12. The appealing properties of organic reactions in aqueous media include their
synthetic advantages as well as unique reactivity and selectivity that are not
often attained under dry conditions, making then profitable in many cases.
Thus, water-based organic reactions have been gaining popularity in synthetic
chemistry, particularly for its abundant availability, and for its inexpensiveness.
For selected reviews on organic reactions in aqueous media, see: (a) Simon, M.
O.; Li, C. J. Chem. Soc. Rev. 2012, 41, 1415; (b) Butler, R. N.; Coyne, A. G. Chem. Rev.
2010, 110, 6302; (c) Lombardo, M.; Trombini, C. Curr. Opin. Drug Disc. 2010, 13,
717; (d) Chanda, A.; Fokin, V. V. Chem. Rev. 2009, 109, 725; (e) Organic Reactions
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15. Trabocchi, A.; Mannino, C.; Machetti, F.; De Bernardis, F.; Arancia, S.; Cauda, R.;
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16. Full spectroscopic and analytical data for compounds not included in this ex-
perimental section are described in Supplementary data.