Gold-catalyzed bis-cyclization of 1,2-diol- or acetonide-tethered alkynes. Synthesis of β-lactam-bridged acetals: A combined experimental and theoretical study

Article abstract of DOI:10.1016/j.tet.2012.03.028

2-Azetidinone-tethered alkyn-1,2-diols or alkynyl acetonides, readily prepared from imines of (R)-2,3-O-isopropylideneglyceraldehyde, were used as starting materials for the regio- and diastereospecific catalytic bis-oxycyclization reaction in the presenc

Full text of DOI:10.1016/j.tet.2012.03.028

Tetrahedron 68 (2012) 10748e10760
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Gold-catalyzed bis-cyclization of 1,2-diol- or acetonide-tethered
alkynes. Synthesis of
b-lactam-bridged acetals: a combined
experimental and theoretical study
,
b
,
a
c
c
Benito Alcaide a , Pedro Almendros , Rocío Carrascosa , Ramon Lopez , María I. Menendez
*
*
ꢀ
ꢀ
ꢀ
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
c
ꢀ
Departamento de Química Física y Analítica, Universidad de Oviedo, Julian Clavería 8, 33006 Oviedo, Asturias, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
2-Azetidinone-tethered alkyn-1,2-diols or alkynyl acetonides, readily prepared from imines of (R)-2,3-O-
isopropylideneglyceraldehyde, were used as starting materials for the regio- and diastereospecific cat-
alytic bis-oxycyclization reaction in the presence of a gold/acid binary system. Interestingly, in contrast to
the gold-catalyzed reactions of N-tethered terminal alkynes, which lead to the corresponding 6,8-
dioxabicyclo[3.2.1]octane derivatives (proximal adduct), the reactions of substituted alkynic diols and
acetonides under identical conditions gave the 7,9-dioxabicyclo[4.2.1]nonane derivatives (distal adducts)
as the sole products, through exclusive 7-endo/5-exo bis-oxycyclizations by initial attack of the oxygen
atom to the external alkyne carbon. Moreover, the mildness of the method allowed the incorporation of
a 1,3-diyne moiety as reactive partner, displaying exquisite chemoselectivity toward the internal alkynic
moiety. In order to confirm the mechanistic proposal, labeling studies with deuterium oxide have been
performed. Besides, density functional calculations were performed to gain insight into the mechanisms
of the bis-oxycyclization reactions.
Received 23 November 2011
Received in revised form 8 March 2012
Accepted 8 March 2012
Available online 15 March 2012
Keywords:
Alkynes
Cyclization
Gold
Lactams
Reaction mechanisms
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
addition of oxygen nucleophiles across a carbonecarbon triple bond
is one of the most rapid and convenient methods for the preparation
b
-Lactams are not only the most commonly prescribed antibac-
of oxacycles.8e10 However, regioselectivity problems may be sig-
terial agents,1 but also exhibit some other biological activities, for
which they are considered as enzyme inhibitors,2 potential chemo-
and neurotherapeutic drugs,3 and gene activation agents.4 These
biological activities, combined with the use of these products as
nificant (endo vs exo cyclization). Following our commitment in
b
-lactams and the synthetic use of metals,11 in this paper we report
a systematic investigation of the gold-catalyzed cyclization of 1,2-
diol- or acetonide-tethered alkynes that establishes a regio- and
stereocontrolled versatile route to a variety of enantiopure tricyclic
starting materials to prepare a- and b-amino acids, alkaloids, het-
erocycles, taxoids, and other types of compounds of biological and
b-lactam-bridged acetals. Depending on the nature of the sub-
medicinal interest,5 provide the motivation to explore new meth-
stituent on the alkyne, two different regioselectivities for the addi-
tion reactions are observed.9e,12a Moreover, the mechanisms of the
bis-oxycyclization reactions have additionally been investigated by
a theoretical study.
odologies for the synthesis of substances based on the b-lactam core.
In addition, bridged acetals are structural units that are extensively
encountered in a number of biologically active natural products,
such as attenol, brevicomin, cyclodidemniserinol, frontalin, multi-
striatin, and pinnatoxin A,6 and therefore, their stereocontrolled
synthesis remains an intensive research area. On the other hand,
alkyne chemistry has attracted considerable attention in recent
years.7 In particular, transition metal-catalyzed intramolecular
2. Results and discussion
Fig. 1 shows the structures of cyclization precursors. Precursors
for the bridged ketal formation, alkynic 1,2-diols 1aee, 2a, and 2b,
dialkynic 1,2-diols 3aed, alkynic acetonides 4aee, 5a, and 5b, and
dialkynic acetonides 6aed, were made starting from imines of (R)-
2,3-O-isopropylideneglyceraldehyde. Terminal alkynic acetonides
4a and 5a were prepared using the ketene-imine cyclization as we
* 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@quim.
ucm.es (B. Alcaide), Palmendros@iqog.csic.es (P. Almendros).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.03.028

B. Alcaide et al. / Tetrahedron 68 (2012) 10748e10760
10749
R2
screening demonstrated that dichloromethane was the best choice
in the reaction (Table 1). The use of a more Lewis acidic gold salt
(AuCl3) as catalyst alone without PTSA was also tested. Thus, we
treated alkynic acetonide 4a with 5 mol % of AuCl3. However,
acetal 10 was obtained in a poor 15% yield.
R
OH
OH
OH
H
H
N
H
H
N
H
H
N
OH
OH
OH
MeO
O
O
R
PMP
R1
O
O
(+)-2a
O
R = H
(+)-2b R = Ph
1 = H, R2 = H
(+)-1a R = H
(–)-1b R = Ph
(+)-1c
(–)-3a
R
OH
(–)-3b R1 = H, R2 = Ph
(–)-3c R1 = Ph, R2 = Ph
(–)-3d
H
H
N
H
H
N
(+)-2c
R = Me
OH
MeO
MeO
R = 2-thiophenyl
i)
O
(–)-1d R = (ethynyl)benzene
O
R
1 = Ph, R2 = H
(+)-1e R = Me
O
O
Me
R
R2
(+)-1a
(–)-10
(65%)
O
O
O
H
H
H
N
H
H
N
O
O
O
MeO
O
O
O
O
H
H
N
H
H
H
H
N
N
O
O
O
R
R1
MeO
MeO
MeO
O
PMP
O
O
i)
O
+
O
(+)-4a R = H
R = Ph
(+)-4c R = 2-thiophenyl
(+)-6a R1 = H, R2 = H
(+)-5a
R = H
R = Ph
(+)-5c R = Me
N
(+)-5b
R
1 = H, R2 = Ph
O
O
Me
O
(+)-4b
(+)-6b
(+)-6c
R
1 = Ph, R2 = Ph
(+)-6d R1 = Ph, R2 = H
(–)-10 (31%)
(+)-4a
(+)-11 (27%)
(+)-4d R = (ethynyl)benzene
(+)-4e
R = Me
O
O
Fig. 1. Structures of alkynic 1,2-diols and alkynic acetonides 1e6. PMP¼4-MeOC6H4.
H
H
N
H
H
N
H
H
N
O
O
MeO
MeO
MeO
ii)
iii)
O
O
previously described.13 Terminal alkynes 4a and 5a were func-
tionalized as their corresponding aryl alkynes 4b, 4c, and 5b or
phenylbuta-1,3-diyne 4d under Sonogashira or CadioteChodkie-
wicz conditions (Schemes S1 and S2, see Supplementary data).
Methyl-substituted alkynyldioxolane 4e was prepared through
O
O
Me
O
(–)-10 (77% for ii; 71% for iii)
(+)-4a
(+)-4a
Scheme 1. Gold catalysis for the bis-cycloetherification of alkynic diol 1a and alkynic
acetonide 4a. Synthesis of bridged hybrid -lactam/acetal 10. Conditions: (i) 2.5 mol %
[AuClPPh3], 2.5 mol % AgOTf, 10 mol % PTSA, CH2Cl2, RT, 1a: 2 h; 4a: 15 h. (ii) 2.5 mol %
[AuClPPh3], 2.5 mol % AgOTf, 10 mol % PTSA or FeCl3, 100 mol % H2O, CH2Cl2, sealed tube,
80 ꢀC, PTSA: 2 h (77% yield); FeCl3: 48 h (50% yield). (iii) 2.5 mol % [AuClPPh3], 2.5 mol %
AgOTf, 100 mol % H2O, CH2Cl2, sealed tube, 80 ꢀC, 2 h. PTSA¼p-Toluenesulfonic acid.
b
base-promoted N-propargylation of the NH-
1-bromobut-2-yne. Starting alkynic acetonide 5c and dialkynic
acetonides 6aed were prepared from 3-hydroxy-
-lactams 814
b-lactam 7b with
b
using selective transformations of the hydroxylic group together
with the Sonogashira protocol (Scheme S3, see Supplementary
data). Diols 1e3 were prepared from acetonides 4e6 through
acetonide hydrolysis (Schemes S1eS3, see Supplementary data).
Our investigation began with alkynic diol 1a as model sub-
strate. 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) at room
temperature could be an excellent cooperative catalytic system
for this purpose (Scheme 1). However, the conversion to the cor-
responding tricyclic acetal 10 could not be satisfied with a Lewis
acid (FeCl3) in the presence of Au(I)/Ag(I). Taking into account the
above success, the more challenging bis-oxycyclization of alkynic
acetonide 4a was tested (Table 1, Scheme 1). To prove this hy-
pothesis, we initially started our investigation by using 2.5 mol %
of Au(PPh3)Cl/AgOTf and 10 mol % of PTSA in CH2Cl2 at room
temperature. To our disappointment, although the reaction
gave bridged ketal 10 as the major product, it was obtained to-
gether with ketone 11, arising from alkyne hydration.15 Gratify-
ingly, after considerable experimentation, it was found that
alkynic acetonide 4a 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 tri-
cyclic ketal 10 through a regio- and diastereospecific 6-exo/5-exo
bis-oxycyclization (Table 1, Scheme 1). Formation of the undesired
ketone 11 was avoided using 100 mol % of water as additive
(Scheme 1). Probably, the presence of water favors the hydrolysis
of intermediate 25 in the mechanistic proposal of Scheme 6,
avoiding alkyne hydration. By contrast to the behavior of alkynic
diol 1a, Brønsted and Lewis acid co-catalysis (PTSA and FeCl3)
were equally effective starting from alkynic acetonide 4a, which
may point to two different pathways for the cyclizations of 1a and
4a. Besides, the reaction of acetonide 4a under gold catalysis in the
absence of acid additive proceeded to afford the corresponding
ketal 10 in just a slightly lower yield (Table 1, Scheme 1). Solvent
Under the optimized reaction conditions, we investigated the
generality of the gold/acid co-catalytic protocol for 1,2-diol- or
acetonide-tethered alkynes 1e4. AgOTf cannot be considered a co-
catalyst because its action is generally assumed to be restricted to
form cationic gold species by anion exchange.16 The comparative
studies of ketals formation with addition of PTSA demonstrated
that the presence of the Brønsted acid gives higher yields, acting
the acid additive as collaborator but not as a catalyst.17 Thus, the
catalytic system may consist of [Au(OTf)PPh3], generated in situ
from [AuClPPh3] and AgOTf. By examining the influence of the R
substituents on the alkyne side chain, we found that substrates
1bee and 4bee bearing aryl, heteroaryl, alkynyl, or alkyl groups
were smoothly transformed into products 12 in reasonable yields
(Scheme 2). Worthy of note, in contrast to the gold-catalyzed re-
actions of terminal alkynic diol 1a and acetonide 4a, which lead to
the 6,8-dioxabicyclo[3.2.1]octane derivative 10 (proximal adduct),
the reactions of substituted alkynic diols 1bee and acetonides
4bee under identical conditions gave the 7,9-dioxabicyclo[4.2.1]
nonane derivatives 12aed (distal adducts) as the products, through
exclusive 7-endo/5-endo bis-oxycyclizations by initial attack of the
oxygen atom to the external alkyne carbon. Although complete
conversion was observed by TLC and 1H NMR analysis of the crude
reaction mixtures, some decomposition was observed on sensitive
bridged oxacycles 12 during purification by flash chromatography,
which may be responsible for the moderate isolated yields. The
competition between the initial 6-exo and 7-endo oxycyclizations is
gained by the latter, despite a priori should be energetically more
demanding. Thus, the results presented in Schemes 1 and 2 point
that there exists a general mode of cyclization, namely the 7-endo/
5-endo bis-oxycyclization, for internal substituted alkynes and the
6-exo/5-endo mode is preferred for terminal alkynes.18 The mild-
ness of the method allowed the incorporation of a 1,3-diyne moiety
as reactive partner, displaying exquisite chemoselectivity toward
the internal alkynic moiety, directing the bis-cycloetherification to

10750
B. Alcaide et al. / Tetrahedron 68 (2012) 10748e10760
Table 1
Selective bis(cyclization) reaction of alkynic dioxolane 4a under modified metal-catalyzed conditionsa
Catalyst (mol %)
Additive
(mol %)
Time (h)
Acid
(mol %)
T (ꢀC)
Solvent
Product
Yield (%)
[PtCl2(CH2]CH2)]2 (2.5)
AgOTf (5)
FeCl3 (10)
TDMPP (5)
d
24
24
24
14
15
2
48
3
2
d
20
20
20
20
20
80
80
80
80
80
80
DCM
DCM
DCM
DCM
DCM
DCM
DCM
THF
10
10
10
10
10/11
10
10
10
10
d
db
d
d
d
d
AuCl3 (5)
d
d
15
31/27
71
50
64
75
60
77
[AuClPPh3]/AgOTf (2.5)
[AuClPPh3]/AgOTf (2.5)
[AuClPPh3]/AgOTf (2.5)
[AuClPPh3]/AgOTf (2.5)
[AuClPPh3]/AgOTf (2.5)
[AuClPPh3]/AgOTf (2.5)
[AuClPPh3]/AgOTf (2.5)
d
PTSA (10)
d
H2O (100)
H2O (100)
H2O (100)
H2O (100)
H2O (100)
H2O (100)
FeCl3 (10)
PTSA (10)
PTSA (10)
PTSA (10)
PTSA (10)
DCE
Toluene
DCM
4
2
10
10
PTSA¼p-Toluenesulfonic acid, TDMPP¼tris(2,6 dimethoxyphenyl)phosphine, DCM¼dichloromethane, THF¼tetrahydrofuran, DCE¼1,2-dichloroethane.
a
Yield of pure, isolated product with correct analytical and spectral data.
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.
b
the exclusive formation of tricyclic ketal 12c. The structure and
stereochemistry of the bridged tricycle 12a were unequivocally
R
R
R
O
O
established by X-ray crystallographic studies (Fig. S1, see Supple-
O
mentary data).19
OH
H
H
H
N
H
H
N
O
O
O
OH
O
O
i)
ii)
N
PMP
PMP
PMP
O
O
OH
O
H
H
N
H
H
N
H
H
N
OH
O
O
(+)-2a R = H
MeO
MeO
MeO
(+)-13a
(+)-5a
R = H
(+)-5b
(63% from diol; 59% from acetonide)
(60% from diol; 55% from acetonide)
(+)-13c (62% from diol; 58% from acetonide) (+)-5c R = Me
O
i)
ii)
(+)-2b
R = Ph
R = Me
(+)-13b
R = Ph
R
(+)-2c
R
R
O
O
O
(+)-12a
(+)-12b
(–)-1b R = Ph
(60% from diol; 63% from acetonide) (+)-4b R = Ph
(52% from diol; 58% from acetonide) (+)-4c
R =
(58% from diol; 63% from acetonide) (+)-4e R = Me
Scheme 3. Gold catalysis for the bis-cycloetherification of alkynic diols 2 and alkynic
acetonides 5. Synthesis of bridged hybrid -lactam/acetals 13. Conditions: (i) 2.5 mol %
[AuClPPh3], 2.5 mol % AgOTf, 10 mol % PTSA, CH2Cl2, RT, 2a: 4 h; 2b: 5 h; 2c: 4 h. (ii)
2.5 mol % [AuClPPh3], 2.5 mol % AgOTf, 10 mol % PTSA, 100 mol % H2O, CH2Cl2, sealed
tube, 80 ꢀC, 5a: 2 h; 5b: 3 h; 5c: 3 h. PMP¼4-MeOC6H4. PTSA¼p-Toluenesulfonic acid.
(+)-1c
R = Thp
R =
R = Thp
b
(–)-1d
(+)-12c (50% from diol; 52% from acetonide) (+)-4d
(+)-12d
Ph
Ph
(+)-1e R = Me
Scheme 2. Gold catalysis for the bis-cycloetherification of alkynic diols 1bee and al-
kynic acetonides 4bee. Synthesis of bridged hybrid -lactam/acetals 12. Conditions: (i)
b
2.5 mol % [AuClPPh3], 2.5 mol % AgOTf, 10 mol % PTSA, CH2Cl2, RT, 1b: 3 h; 1c: 3 h; 1d:
2 h; 1e: 3 h. (ii) 2.5 mol % [AuClPPh3], 2.5 mol % AgOTf, 10 mol % PTSA, 100 mol % H2O,
CH2Cl2, sealed tube, 80 ꢀC, 4b: 3 h; 4c: 3 h; 4d: 2 h; 4e: 2 h. PTSA¼p-Toluenesulfonic
acid, Thp¼2-thiophenyl.
corresponding tricyclic acetals, which would be formed by com-
petitive cyclization of the contiguous dioxygenated functionality to
one of the two triple bonds catalyzed by gold(I). Thus, we found
that the reaction of bis-alkynes 3 and 6 bearing or not phenyl
groups at the terminus of the alkyne, also proceeded smoothly to
selectively give products 14e18 (Scheme 4).21 During the course of
this study, a remarkable substituent effect was discovered: the bis-
oxycyclization exclusively occurred at the unsubstituted alkynic
When alkyne substituent was moved from position N1 to C3, as
in 3,4-tethered diols 2 and acetonides 5, they furnished the corre-
sponding bridged ketal systems 13 in fair yields and as only one
isomer in their reactions with the gold catalytic system (Scheme 3).
Significantly, both substituted and unsubtituted alkynes at the
terminal position followed the same regiochemical pattern, yield-
ing proximal adducts as sole bis-cycloetherification reaction
products. Although we suspected that the regioselectivity for the
substituted alkynic diols 2b and 2c and its corresponding dioxo-
lanes 5b and 5c would be the same as the previous set of experi-
ments for 1,4-tethered alkynyl derivatives 1 and 4, we found that in
the former case tricyclic acetals 13b and 13c (proximal adducts)
were obtained as single regio- and diastereomers. Thus, by using
a related alkynic diol or acetonide homologue (2b, 2c or 5b, 5c vs
1b, 1e or 4b, 4e), the regioselectivity can be reversed, favoring the
7-exo/5-endo bis-oxycyclization of the acetonide group toward the
internal alkyne carbon (proximal adduct) over the 8-endo/5-endo
bis-oxycyclization toward the external alkyne carbon (distal ad-
duct). The exclusive formation of proximal adducts 13b and 13c
when the distance between the dioxolane group and the alkyne
moiety was increased, would be interpreted by considering the ring
size of the intermediates (seven-membered vs eight-membered
rings). Probably, the combination of developing ring strain and
the requirement to restrict rotations around flexible bonds in the
bridged 8,10-dioxabicyclo[5.2.1]decane system ensures unfavor-
Me
O
O
O
O
H
H
N
H
H
N
H
H
N
H
O
O
O
O
O
O
i)
O
O
O
O
+
+
O
N
O
O
Me
O
Me
(
–)-14 (36%)
(–
)-15a (29%)
(+)-16a (27%)
(+)-6a
Ph
R2
Ph
O
H
H
N
H
H
H
H
N
O
O
O
O
O
O
i)
i)
O
O
6c
6b
N
Ph
R1
O
O
O
Me
(+)-6b R1 = H, R2 = Ph
(+)-17 (48%)
(–)-15b (63%)
1 = Ph, R2 = Ph
(+)-6c
R
(+)-6d
R
1 = Ph, R2 = H
6d i)
Me
Me
O
O
O
O
H
H
O
O
O
O
+
N
N
Ph
Ph
O
able enthalpic and entropic contributions to
DG, avoiding its
(+)-16b
(+)-18
(52%)
(37%)
formation.20
Scheme 4. Gold catalysis for the bis-cycloetherification of bis-alkynic acetonides
Upon further exploring the applicability of this bis-
cycloetherification reaction, in addition to mono-alkynes, bis-
alkynic diols 3 and acetonides 6 were also examined to obtain the
6aed. Synthesis of bridged hybrid b-lactam/acetals 14e18. Conditions: (i) 2.5 mol %
[AuClPPh3], 2.5 mol % AgOTf, 10 mol % PTSA, 100 mol % H2O, CH2Cl2, sealed tube, 80 ꢀC,
3 h. PTSA¼p-Toluenesulfonic acid.

B. Alcaide et al. / Tetrahedron 68 (2012) 10748e10760
10751
H
H
side by treatment of mono-substituted bis-alkynic acetonides
6b and 6d under gold/acid co-catalysis. Besides, the bis-
hydroalkoxylation of 1,4-tethered bis-alkynic precursors 6b and
6c takes place preferentially or solely over the competitive reaction
on the corresponding 3,4-tethered moiety. Thus, the chemo-
selectivity was uniformly high, being possible to direct the tricycle
formation by the substitution. In agreement with above results
(Schemes 1 and 2), different regioselectivity was observed for non-
substituted alkyne 6b and substituted alkyne 6c. As can be seen
from Scheme 4, tricycles 14, 16a, and 16b bearing a ketonic side-
chain were also formed because of further gold-catalyzed hydra-
tion of the initially unreacted alkyne moiety.15 Similar results were
obtained using bis-alkynic diols 3aed.
Bis-cycloetherification of alkynic 1,2-diols 1e3, catalyzed by the
gold system was not significantly less effective than was the gold
catalysis for the bis-hydroalkoxylation of alkynic acetonides 4e6.
Control experiments, however, ruled out the presence of a diol
intermediate formed in the gold-catalyzed bis-oxycyclization of
alkynic acetonides: diol 1a did react in dichloromethane at 80 ꢀC on
a sealed tube in the presence of [AuClPPh3] (2.5 mol %)/AgOTf
(2.5 mol %)/FeCl3 (10 mol %)/H2O (100 mol %) to afford a complex
mixture of products, in which the tricyclic acetal 10 was not
detected. Besides, no reaction occurred on heating a solution of the
above diol in dichloromethane at 80 ꢀC in a sealed tube in the
presence of [AuClPPh3] (2.5 mol %)/AgOTf (2.5 mol %)/FeCl3
(10 mol %). The fact that the reaction of acetonide 4a catalyzed by
R2
O
OH
O
O
H
H
N
R2
O
OH
R1
N
proton
transf er
12
R1
1
AuPPh3
H
H
N
R2
H
O
O
R1
AuPPh3
OH
O
H
H
N
R2
OH
5-endo
23
oxycyclization
OH
O
R1
AuPPh3
O
H
H
19
R2
R1
N
7-endo
O
alkoxyauration
OH
AuPPh3
22
isomerization
H
H
N
H
R2
O
X
R1
AuPPh3
proton
transf er
O
20
OH
H
H
R2
O
+
AuPPh3
O
R1
N
21
Scheme 5. Mechanistic explanation for the gold-catalyzed bis-cycloetherification of
alkynic diols 1.
the
p-philic gold complex [Au(OTf)PPh3] alone, in the absence of
acid additive, proceeded to afford the corresponding ketal 10, may
also support this order of steps: the acetal attacks the activated
alkyne and the resulting oxonium cation then is hydrolyzed.
A possible mechanism for the achievement of tricyclic ketals 12
H
H
R2
O
O
O
O
H
H
N
R2
O
O
R1
N
proton
transf er
involving a gold-based carbophilic
p-acid may proceed through
12
R1
initial
h
2-coordination of the metal to the triple bond of alkynic
4
AuPPh3
H
H
N
diols 1 leading to intermediates 19. Next, 7-endo alkoxyauration
forms intermediates 20. Vinylmetal species 20 did not evolve
through demetalation and proton transfer generating the methyl-
enic oxacycle 21 and releasing the gold catalyst. By contrast, rear-
rangement of species 20 generates the isomeric metalaoxonium 22,
enhancing the electrophilicity of the unsaturated moiety. Sub-
sequent intramolecular nucleophilic attack of the primary alcohol
to the carbonylic-like position from the less hindered face would
form complex 23. Demetalation linked to proton transfer liberates
adduct 12 with concomitant regeneration of the Au(I) species
(Scheme 5). Triflate assisted proton transfer from intermediates 23
to the final products 12 may also be considered.
R2
H
O
O
R1
AuPPh3
O
O
5-endo
23
H
H
R2
O
O
oxycyclization
OH
O
N
R1
AuPPh3
H
H
R2
24
R1
N
7-endo
alkoxyauration
O
O
O
AuPPh3
22
H
H
N
R2
O
H2O
acetonide hydrolysis
R1
AuPPh3
A possible pathway for the gold-catalyzed alkynyldioxolane
isomerization
25
cyclization may initially involve the formation of a
p-complex 24
CH3COCH3
through coordination of the gold salt to the triple bond of alkynyl
dioxolanes 1. Next, 7-endo oxymetalation forms enol vinylmetal
species 25. Intermediates 25 did evolve to species 22 through
acetonide hydrolysis and further isomerization; thus, enhancing
the electrophilicity of the resulting moiety. Subsequent intra-
molecular nucleophilic attack of the primary alcohol to the elec-
trophilic position would form complex 23. Demetalation linked to
proton transfer liberates adduct 12,22 closing the catalytic cycle and
releasing the metal catalyst (Scheme 6).
In order to confirm the mechanistic proposal of Scheme 6, we
performed labeling studies with deuterium oxide. When alky-
nyldioxolane 4b was treated under bis-oxycyclization conditions
employing D2O (200 mol %) instead of H2O, adduct 12a with in-
corporation of two deuterium atoms at the methylenic group was
achieved (Scheme 7). This double deuteration caused both the
modification of the peaks at 3.10 and 3.87 ppm, which are the
signals of the NCHH protons, and the disappearance of the peaks at
1.94 and 2.34 ppm, which are the signals of the NCH2CHH protons,
on the 7,9-dioxabicyclo[4.2.1]nonane 12a. Deuterium labeling
Scheme 6. Mechanistic explanation for the gold-catalyzed bis-cycloetherification of
alkynic acetonides 4.
experiment starting from diol 1 was also accomplished, showing
a similar trend to, that is, observed starting from acetonide 4
(Scheme 7). The fact that the gold-catalyzed conversion of alky-
nyldioxolane 4b into tricycle 12a in the presence of 2 equiv of D2O
afforded double deuterated product [D]-12a as judge by 1H NMR
spectroscopy and mass spectrometry (see Supplementary data),
suggests that deuteration of the double bond in species 25 as well
as deuterolysis of the carbonegold bond in intermediate [D]-23
have occurred (Scheme S4, see Supplementary data).
Theoretical calculations confirm the mechanistic proposals
shown in Schemes 5 and 6 for the gold-catalyzed bis-oxycyclization
of 1,2-diol- and acetonide-alkynes (see Computational Methods for
details). Figs. 2 and 3 display the Gibbs energy profiles in CH2Cl2
solution for both reactions along with the structure of some rele-
vant intermediates and transition states (TSs), and all the optimized

10752
B. Alcaide et al. / Tetrahedron 68 (2012) 10748e10760
OH
which involves a 1,3-H shift from the oxygen atom to the gold-
linked carbon atom of the seven-membered ring, is only energeti-
cally accessible thanks to the presence of BSA. When this acid is not
present, we located a TS, TS-20e210 (49.3 kcal/mol above the in-
termediate 19), for a 1,2-H migration from the oxygen atom to the
carbon atom bearing the R1¼H substituent. This TS evolves to
a minimum energy structure, 210 (e17.6 kcal/mol relative to iso-
lated reactants), which would not lead to the formation of product
12. A bis-oxycyclization has happened at 210, but the formation of
product 12 does not occur because at 210 both oxygen atoms bond
to different C atoms. On the other hand, 210 is different from
structure 21 proposed in Scheme 5. Therefore, our theoretical re-
sults clearly show the crucial role played by the Brønsted acid in the
bis-oxycyclization of 1.
H
H
H
N
H
H
N
OH
MeO
MeO
O
2.5 mol% [AuClPPh3], 2.5 mol% AgOTf
O
O
D
10 mol% PTSA, 200 mol% D2O
CH2Cl2, RT, 3 h
Ph
Ph
Ph
O
D
(–)-1b
(+)-[D]-12a (54%)
O
H
H
H
N
O
MeO
O
2.5 mol% [AuClPPh3], 2.5 mol% AgOTf MeO
10 mol% PTSA, 200 mol% D2O
O
O
D
N
Ph
CH2Cl2, sealed tube, 80 oC, 3 h
O
D
(+)-4b
(+)-[D]-12a (65%)
Scheme 7. Au(I)-catalyzed bis-oxycyclization reactions of alkynyldiol and alky-
nyldioxolane derivatives 1b and 4b in presence of D2O.
Fig. 2. Gibbs energy profile in CH2Cl2 solution obtained for the gold-catalyzed bis-cyclization of the alkynic 1,2-diols 1 at the M06/6e31þG(d) (def2-SVP for Au) theory level. All the
energies are referred to the reactants: alkynic 1,2-diol (1a)þ[Au(OTf)PH3]þbenzenesulfonic acid (BSA).
geometries are collected in the Supplementary data. For the alkynic
diol 1, five reaction steps have been found. The first one, charac-
terized by the TS TS-1e19 for the Au coordination, presents a small
barrier of 1.9 kcal/mol relative to isolated reactants. From this point
and along the whole energy profile the triflate anion is clearly
separated from the gold(I)-phosphine moiety and from the hot
reacting points, so it certainly should not be considered a co-
catalyst of the process. At the TSs TS-19e20 and TS-22e23 two
internal oxycyclizations (7-endo and 5-endo, respectively) are per-
formed, with energy barriers of 17.5 and 13.3 kcal/mol measured
from their corresponding previous intermediates. Opposite to these
energetically smooth processes, the most demanding steps are
those involving internal rearrangements or proton transfers,
TS-20e22-BSA and TS-23e12, with energy barriers in solution of
38.8 and 28.8 kcal/mol, respectively, from the most stable previous
intermediate obtained by us, 19 (14.6 kcal/mol under reactants).
TS-20e22-BSA corresponds to the rate determining step of the
overall reactive process collected in Scheme 5. It is also interesting
to note that, TS-20e22-BSA, 24.2 kcal/mol above reactants, implies
the presence of the Brønsted benzenesulfonic acid (BSA). In effect,
according to our theoretical results the passage from 20 to 22,
For the reaction of alkynic acetonides 4, the first step is also the
gold coordination to the triple CeC bond, characterized by
TS-4e24, which connects a loose initial complex (2.2 kcal/mol
under reactants) with a tighter one (9.8 kcal/mol under reactants).
TS-24e25 performs the first 7-endo internal cyclization, with an
energy barrier of 13.3 kcal/mol from its previous intermediate, to
form the enol vinylmetal species named 25a in Fig. 3 (1.4 kcal/mol
under reactants). Once again the triflate anion is relatively far from
both the gold(I)-phosphine moiety and the hot reacting points. No
diol intermediates have been theoretically located before the first
cyclization along the bis-oxycyclization of 4,23 as 24 evolves to the
cyclic intermediate 25a, where one of the CeO bonds in the ace-
tonide ring is elongated. To go step forward along the reaction
profile the explicit inclusion of three water molecules is needed, so
intermediate 25a becomes 25b when those water molecules are
added. This addition definitely breaks the acetonide ring and pro-
vokes the necessary rearrangements to facilitate the subsequent
hydrolysis performed by water molecules. TS-25e22.1 and
TS-25e22.2 represent the two reaction steps involved in the ad-
dition of one water molecule to the system along with the elimi-
nation of dimethyl ketone. At TS-25e22.1 a water molecule is

B. Alcaide et al. / Tetrahedron 68 (2012) 10748e10760
10753
Fig. 3. Gibbs energy profile in CH2Cl2 solution obtained for the gold-catalyzed bis-cyclization of the alkynic acetonides 4 at the M06/6e31þG(d) (def2-SVP for Au) theory level. All
the energies are referred to the reactants: alkynic acetonide (4a)þ[Au(OTf)PH3]þwater molecules when necessary.
added to the double bond bearing the gold catalyst and at
TS-25e22.2 an OHꢁ group bonds to the C atom external to the
seven-membered ring, while dimethyl kenote leaves. Between both
TSs we located a stable intermediate I-25e22, 22.4 kcal/mol under
reactants. TS-25e22.1 and TS-25e22.2, are 25.2 and 3.8 kcal/mol
over reactants energy, respectively. TS-25e22.1 corresponds to the
rate-limiting step of the overall process shown in Scheme 6 with
a value of 35.0 kcal/mol measured from the most stable previous
intermediate, 24. This value is similar to that found for reactant 1, in
accordance with the similar reaction times experimentally ob-
served when 1 is allowed to react in presence of PTSA and 4 in
presence of water, as considered in our calculations. TS-25e22.2
straight yields a water adduct of 22, 22b in Fig. 3, without the re-
leasing of the gold catalyst. Eventually, evolution from 22 to the
final product 12 goes through the same two final steps as for diol 1,
those described by TS-22e23 and TS-23e12.
confirmed by labeling studies with deuterium oxide. Moreover,
theoretical calculations are in agreement with the mechanistic
explanations.
4. Computational methods
The computational investigation was carried out with the sim-
plified species Au(OTf)PH3 and benzenesulfonic acid (BSA), which
were chosen to mimic the Au(OTf)PPh3 catalyst and the PTSA
Brønsted acid experimentally used, respectively. These simplifica-
tions not only minimize the computational time but also make
possible computations involving the catalyst and/or the Brønsted
acid linked to the alkynic reagents without any significant changes
in the obtained theoretical results. In particular, a recent theoretical
study on the hydroamination of alkenes catalyzed by gold(I)-
phosphine has proved the adequacy of replacing the PPh3 ligand
by the PH3 one.24 Besides, the Brønsted acid theoretically
employed, BSA, reasonably represents the main features of the
experimental one PTSA on the basis of similar pKa values.
3. Conclusions
In conclusion, we have developed efficient catalytic systems
based on precious metal salts for the synthesis of a variety of
All the quantum chemical computations were carried out with
the Gaussian 09 series of programs.25 Full geometry optimizations
of stable species and TSs were performed in the gas phase by
employing the hybrid density functional M0626 in conjunction with
the standard 6e31þG(d) basis set for the non-metal atoms27 and
the def2-SVP pseudopotential for the gold center.28 This compu-
tational scheme is strongly supported by similar theory levels used
to investigate related gold-containing systems.29 Besides, relativ-
istic calculations were done using the DouglaseKrolleHess (DKH)
enantiopure tricyclic
b-lactam-fused acetals, through regio- and
stereocontrolled bis-oxycyclization reactions. The addition of
a catalytic amount of PTSA to the gold catalyst improves the cyclo-
ketalization acting the acid additive as collaborator. Besides, the
mildness of the method allowed the incorporation of a 1,3-diyne
moiety as reactive partner, displaying exquisite chemoselectivity
toward the internal alkynic moiety. The mechanistic proposal was

10754
B. Alcaide et al. / Tetrahedron 68 (2012) 10748e10760
second order scalar relativistic method30 and the Gaussian nuclear
model31 as implemented in Gaussian 03; finding no significant
changes in the relative energies involved in the rate determining
energy barrier for the gold-catalyzed bis-cyclization of the alkynic
1,2-diol 1 (see Table S3 in Supplementary data). A similar result
could be expected for the acetonide reaction. The nature of the
stationary points was verified by analytical harmonic frequency
calculations. The intrinsic reaction coordinate (IRC) algorithm was
used to check the two minimum energy structures connecting each
TS.32 To take into account condensed-phase effects, single-point
calculations were also carried out on the gas-phase optimized ge-
ometries using the conductor-like polarizable continuum model
(CPCM) with the united atom-Kohm-Sham (UAKS) parametriza-
tion.33 A relative permittivity of 8.93 was assumed in the calcula-
tions to simulate dichloromethane as the solvent experimentally
used. All energies given in the text correspond to the energy in-
cluding the effect of the bulk solvent, which was obtained by
adding the contribution of the Gibbs energy of solvation to the gas-
phase total energies.
66.9, 61.6, 59.1, 55.2, 26.5, 24.7, 3.5. IR (CHCl3)
HRMS (ESI): calcd for [C19H23NO5]þ 345.1576, found 345.1571.
n .
1746, 2223 cmꢁ1
5.2.1.2. Propargylic ether (þ)-6a. From 200 mg (0.89 mmol) of
hydroxy-
-lactam (ꢁ)-8b, and after chromatography of the residue
using hexanes/ethyl acetate (2:1) as eluent gave the propargylic
ether (þ)-6a (142 mg, 61%) as a colorless oil. [ D þ7.5 (c 1.6, CHCl3).
1H NMR (300 MHz, CDCl3, 25 ꢀC)
4.77 (d, J¼5.1 Hz, 1H), 4.33 (t,
b
a
]
d
J¼2.4 Hz, 2H), 4.29 and 3.86 (dd, J¼17.4, 2.5 Hz, each 1H), 4.25 (m,
1H), 4.08 (dd, J¼8.9, 6.6 Hz,1H), 3.80 (m,1H), 3.71 (dd, J¼8.9, 5.0 Hz,
1H), 2.49 (t, J¼2.3 Hz, 1H), 2.22 (t, J¼2.5 Hz, 1H), 1.42 and 1.29 (s,
each 3H). 13C NMR (75 MHz, CDCl3, 25 ꢀC)
d 166.1, 109.6, 79.9, 78.3,
76.6, 76.4, 75.8, 72.1, 66.5, 59.1, 58.4, 30.4, 26.7, 25.0. IR (CHCl3)
n
3310, 1744 cmꢁ1. HRMS (ESI): calcd for [C14H17NO4]þ 263.1158,
found 263.1152.
5.2.1.3. Propargylic ether (þ)-6b. From 134 mg (0.44 mmol) of
hydroxy-
b
-lactam (ꢁ)-9, and after chromatography of the residue
using hexanes/ethyl acetate (3:1) as eluent gave the propargylic
ether (þ)-6b (121 mg, 66%) as a yellow oil. [ D þ7.6 (c 0.2, CHCl3).
1H NMR (300 MHz, CDCl3, 25 ꢀC)
7.34 (m, 2H), 7.28 (m, 3H), 4.84
a]
5. Experimental section
5.1. General information
d
(d, J¼5.3 Hz, 1H), 4.54 and 4.04 (d, J¼17.4 Hz, each 1H), 4.53 (s, 2H),
4.31 (m, 1H), 4.10 (dd, J¼8.9, 6.6 Hz, 1H), 3.85 and 3.73 (dd, J¼9.1,
5.0 Hz, each 1H), 1.42 and 1.28 (s, each 3H). 13C NMR (75 MHz,
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
CDCl3, 25 ꢀC)
d
166.5, 131.7, 131.6, 128.7, 128.4, 128.3, 128.2, 122.4,
122.0, 87.4, 83.8, 83.6, 80.0, 76.7, 66.7, 59.3, 59.2, 31.3, 26.9, 26.1. IR
(CHCl3)
2190, 1745 cmꢁ1. HRMS (ESI): calcd for [C20H21NO4]þ
n
339.1471, found 339.1467.
(
13C, 76.9 ppm). Low and high resolution mass spectra were taken
5.2.1.4. Propargylic ether (þ)-6c. From 99 mg (0.44 mmol) of
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
hydroxy-
b
-lactam (ꢁ)-8b, and after chromatography of the residue
using hexanes/ethyl acetate (4:1) as eluent gave the propargylic
ether (þ)-6c (96 mg, 64%) as a colorless oil. [ D þ4.5 (c 0.2, CHCl3).
1H NMR (300 MHz, CDCl3, 25 ꢀC)
7.45 (m, 2H), 7.33 (m, 3H), 4.91
a
]
spectrometer. Specific rotation [
a
]
D is given in 10ꢁ1 deg cm2 gꢁ1 at
d
20 ꢀC, and the concentration (c) is expressed in g per 100 mL. All
commercially available compounds were used without further
purification.
(m, 1H), 4.60 (s, 2H), 4.33 (m, 2H), 4.16 (m, 1H), 3.89 (m, 2H), 3.79
(dd, J¼8.9, 5.1 Hz, 1H), 2.24 (m, 1H), 1.48 and 1.35 (s, each 3H). 13C
NMR (75 MHz, CDCl3, 25 ꢀC)
d 166.5, 131.8, 128.7, 128.3, 122.0, 109.7,
87.4, 83.6, 80.0, 76.8, 76.6, 72.2, 66.7, 59.3, 59.2, 30.5, 26.8, 25.1. IR
(CHCl3) HRMS (ESI): calcd for
3305, 2194, 1745 cmꢁ1
[C26H25NO4]þ 415.1784, found 415.1788.
5.2. Experimental procedures
n
.
5.2.1. Base-promoted reaction between propargylic bromides and
hydroxy-
b
-lactams 8 or 9. General procedure for the synthesis of
5.2.1.5. Propargylic ether (þ)-6d. From 114 mg (0.38 mmol) of
hydroxy-
-lactam (ꢁ)-9, and after chromatography of the residue
propargylic ethers 5c and 6aed. Tetrabutyl ammonium iodide
(31.9 mg, 0.086 mmol), 50% aqueous sodium hydroxide (100 mL),
and propargyl bromide, 1-bromobut-2-yne, or (3-bromoprop-1-
ynyl)benzene (13.82 mmol), were sequentially added at room
b
using hexanes/ethyl acetate (3:1) as eluent gave the propargylic
ether (þ)-6d (71 mg, 55%) as a yellow oil. [
a
]
D þ5.1 (c 0.1, CHCl3). 1H
NMR (300 MHz, CDCl3, 25 ꢀC)
d
7.33 (m, 2H), 7.22 (m, 3H), 4.77 (d,
temperature to a solution of the appropriate hydroxy-
b
-lactam 8 or
J¼5.3 Hz, 1H), 4.53 and 4.04 (d, J¼17.5 Hz, each 1H), 4.32 (t,
J¼2.0 Hz, 1H), 4.28 (m, 1H), 4.07 (m, 1H), 3.85 and 3.71 (dd, J¼9.1,
5.0 Hz, each 1H), 2.44 (t, J¼2.3 Hz,1H),1.43 and 1.28 (s, each 3H). 13C
9 (8.64 mmol) in dichloromethane (100 mL). The reaction was
stirred for 15 h and then water was added (50 mL), before being
partitioned between dichloromethane and water. The aqueous
phase was extracted with dichloromethane (3ꢂ50 mL), the com-
bined organic extracts were washed with brine, dried (MgSO4), and
concentrated under reduced pressure. Chromatography of the
residue using ethyl acetate/hexanes mixtures as eluent gave ana-
lytically pure compounds 5 or 6. Spectroscopic and analytical data
for some representative forms of 5 or 6 follow.
NMR (75 MHz, CDCl3, 25 ꢀC)
d 166.3, 131.7, 128.5, 128.2, 122.4, 109.7,
83.9, 82.1, 79.9, 78.4, 76.6, 75.8, 66.6, 59.1, 58.5, 31.4, 27.0, 25.2. IR
(CHCl3) HRMS (ESI): calcd for
3300, 2190, 1742 cmꢁ1
[C20H21NO4]þ 339.1471, found 339.1473.
n
.
5.2.2. Palladium-catalyzed reaction between iodoarenes and termi-
nal alkynes (þ)-4a, (þ)-5a, and (ꢁ)-8. General procedure for the
synthesis of aryl-substituted alkynes (þ)-4b, (þ)-4c, (þ)-5b, and
(ꢁ)-9. PdCl2(PPh3)2 (7 mg, 0.01 mmol), CuI (3.8 mg, 0.02 mmol),
and triethylamine (60.6 mg, 0.6 mmol) were sequentially added to
a solution of the corresponding terminal alkyne 4, 5, or 8
(1.0 mmol) and the appropriate iodoarene (1.0 mmol) in acetoni-
trile (0.8 mL), under argon atmosphere. The reaction mixture was
stirred at room temperature. After completion of the reaction as
indicated by TLC, the mixture was poured into water (5 mL) and
extracted with ethyl acetate (3ꢂ5 mL). The organic layer was
washed with water (2ꢂ10 mL) and brine (2ꢂ0 mL), dried over
5.2.1.1. Propargylic ether (þ)-5c. From 253 mg (0.86 mmol) of
hydroxy-
b
-lactam (þ)-8a, and after chromatography of the residue
using ethyl acetate/hexanes (1:2) as eluent gave the propargylic
ether (þ)-5c (240 mg, 81%) as a pale yellow solid. Mp 91e93 ꢀC. [
a]
D
þ18.3 (c 0.4, CHCl3). 1H NMR (300 MHz, CDCl3, 25 ꢀC)
d 7.62 and
6.83 (d, J¼9.0 Hz, each 2H), 4.88 (d, J¼5.6 Hz, 1H), 4.36 (s, 3H), 4.25
(dd, J¼8.9, 6.8 Hz,1H), 4.18 (m, 1H), 3.76 (m, 1H), 3.75 (s, 3H), 1.85 (t,
J¼2.3 Hz, 3H), 1.51 and 1.31 (s, each 3H). 13C NMR (75 MHz, CDCl3,
25 ꢀC)
d 164.6, 156.2, 131.0, 119.3, 113.7, 109.5, 83.9, 78.7, 76.9, 73.7,

B. Alcaide et al. / Tetrahedron 68 (2012) 10748e10760
10755
MgSO4, and concentrated under reduced pressure. Chromatogra-
phy of the residue eluting with hexanes/ethyl acetate mixtures gave
analytically pure aryl-substituted alkynes 4, 5, and 9.
stirred for 12 h and then NaHCO3 (aq satd) was added (1 mL), before
being partitioned between ethyl acetate and water. The aqueous
phase was extracted with ethyl acetate (3ꢂ10 mL), the combined
organic extracts were washed with brine, dried (MgSO4), and con-
centrated under reduced pressure. Chromatography of the residue
using ethyl acetate/hexanes (1:2) as eluent gave 113 mg (50%) of
analytically pure compound (þ)-4e as a pale yellow solid. Mp
5.2.2.1. Phenyl-substituted alkyne (þ)-4b. From 261 mg
(1.09 mmol) of terminal alkyne (þ)-4a, and after chromatogra-
phy of the residue using hexanes/ethyl acetate (3:1) as eluent
gave the phenylprop-2-ynyl dioxolane (þ)-4b (235 mg, 68%) as
133e134 ꢀC. [
a
]D þ21.4 (c 0.2, CHCl3).1H NMR (300 MHz, CDCl3, 25ꢀC)
a pale yellow solid. Mp 83e85 ꢀC. [
a
]
þ2.3 (c 0.7, CHCl3). 1H
d
4.39 (d, J¼5.1 Hz,1H), 4.26 (m, 2H), 4.06 (dd, J¼8.8, 6.6 Hz,1H), 3.77
D
NMR (300 MHz, CDCl3, 25 ꢀC)
d
7.33 (m, 5H), 4.59 and 4.09 (d,
(m, 2H), 3.65 (dd, J¼8.8, 5.1 Hz,1H), 3.49 (s, 3H),1.75 (t, J¼2.4 Hz, 3H),
J¼17.3 Hz, each 1H), 4.45 (d, J¼5.1 Hz, 1H), 4.33 (ddd, J¼11.5, 6.6,
4.9 Hz, 1H), 4.10 (dd, J¼8.8, 6.6 Hz, 1H), 3.85 and 3.70 (dd, J¼9.0,
5.0 Hz, each 1H), 3.52 (s, 3H), 1.48 and 1.34 (s, each 3H). 13C NMR
1.48 and 1.30 (s, each 3H). 13C NMR (75 MHz, CDCl3, 25 ꢀC)
d
166.6,
109.5, 82.9, 79.7, 76.7, 72.1, 66.6, 59.0, 30.8, 26.8, 25.1, 3.2. IR (CHCl3)
n
1744, 2224 cmꢁ1. HRMS (ESI): calcd for [C13H19NO4]þ 253.1314, found
253.1314.
(75 MHz, CDCl3, 25 ꢀC)
d 166.7, 131.6, 128.4, 128.2, 122.4, 109.6,
83.8, 83.1, 82.2, 76.7, 66.6, 59.2, 59.1, 31.2, 26.9, 25.1. IR (CHCl3)
n
1745, 2220 cmꢁ1. HRMS (ESI): calcd for [C18H21NO4]þ 315.1471,
found 315.1468.
5.4. Procedure for the synthesis of bromoalkynyl-b-lactam
(D)-7a
5.2.2.2. 2-Thiophenyl-substituted alkyne (þ)-4c. From 250 mg
(1.05 mmol) of terminal alkyne (þ)-4a, and after chromatography
of the residue using hexanes/ethyl acetate (2:1) as eluent gave the
2-thiophenylprop-2-ynyl dioxolane (þ)-4c (266 mg, 79%) as a pale
To a solution of the alkynyl 2-azetidinone (þ)-4a (0.37 mmol) in
acetone (2.5 mL) were added NBS (0.094 g, 0.46 mmol) and silver
acetate (0.019 g, 0.11 mmol). The reaction mixture was stirred at
room temperature in the dark until disappearance (TLC) of the
starting material. The solids were removed by filtration through
a Celite pad (washing with ethyl acetate). The combined organic
filtrates were washed with water and brine, dried (Na2SO4), con-
centrated under reduced pressure, and then purified by column
chromatography eluting with ethyl acetate/hexanes (3/1) to give
orange solid. Mp 122e124 ꢀC. [
a]
þ1.3 (c 0.6, CHCl3). 1H NMR
D
(300 MHz, CDCl3, 25 ꢀC)
d
7.21 (dd, J¼5.1, 1.0 Hz, 1H), 7.15 (dd, J¼3.7,
1.0 Hz, 1H), 6.92 (dd, J¼5.1, 3.7 Hz, 1H), 4.58 and 4.09 (d, J¼17.5 Hz,
each 1H), 4.44 (d, J¼5.1 Hz, 1H), 4.30 (m, 1H), 4.10 (m, 1H), 3.82 and
3.68 (dd, J¼9.0, 5.1 Hz, each 1H), 3.50 (s, 3H), 1.48 and 1.32 (s, each
3H). 13C NMR (75 MHz, CDCl3, 25 ꢀC)
d 166.6, 132.2, 127.2, 126.8,
122.3, 109.6, 86.2, 83.0, 77.1, 76.6, 66.5, 59.2, 59.1, 31.3, 26.9, 25.1. IR
95 mg (81%) of analytically pure bromoalkynyl-
a pale yellow oil.
b-lactam (þ)-7a as
(CHCl3)
n
1744, 2225 cmꢁ1. HRMS (ESI): calcd for [C16H19NO4S]þ
321.1035, found 321.1029.
5.4.1. Bromoalkynyl-
b
-lactam (þ)-7a. [
a
]
þ28.2 (c 0.4, CHCl3). 1H
D
5.2.2.3. Phenyl-substituted alkyne (þ)-5b. From 64 mg
(0.19 mmol) of terminal alkyne (þ)-5a, and after chromatography of
the residue using hexanes/ethyl acetate (3:1) as eluent gave the
phenylprop-2-ynyl dioxolane (þ)-5b (65 mg, 84%) as a yellow oil.
NMR (300 MHz, CDCl3, 25 ꢀC)
d
4.46 (d, J¼5.1 Hz, 2H), 4.38 and 3.92
(d, J¼17.3 Hz, each 1H), 4.30 (m, 1H), 4.11 (dd, J¼8.8, 6.5 Hz, 1H),
3.80 and 3.70 (dd, J¼9.0, 5.0 Hz, each 1H), 3.53 (s, 3H), 1.48 and 1.35
(s, each 6H). 13C NMR (CDCl3)
d 166.7, 109.7, 83.1, 76.6, 73.3, 66.7,
[
a
]
D þ8.2 (c 0.4, CHCl3). 1H NMR (300 MHz, CDCl3, 25 ꢀC)
d
7.67 and
59.5, 59.2, 43.7, 31.5, 26.9, 25.1. IR (CHCl3) n
1742 cmꢁ1. HRMS (ESI):
6.86 (d, J¼9.0 Hz, each 2H), 7.33 (m, 3H), 5.00 (d, J¼5.6 Hz, 1H), 4.68
calcd for [C12H16BrNO4]þ 317.0263, found 317.0270.
(s, 2H), 4.29 (m, 3H), 3.84 (dd, J¼8.6, 5.9 Hz, 1H), 3.78 (s, 3H), 1.53
and 1.34 (s, each 3H). 13C NMR (75 MHz, CDCl3, 25 ꢀC)
d 164.6, 156.5,
131.8, 131.0, 128.8, 128.3, 119.5, 113.9, 109.7, 87.5, 83.5, 79.0, 77.6,
5.5. Copper(I) chloride promoted heterocoupling reaction
between 2-azetidinone-tethered alkyne (D)-7a and
phenylacetylene. Procedure for the synthesis of 1,3-diyne-
lactam (D)-4d
67.0, 61.8, 59.4, 55.3, 26.7, 24.9. IR (CHCl3) n
1743, 2222 cmꢁ1. HRMS
(ESI): calcd for [C24H25NO5]þ 407.1733, found 407.1726.
b-
5.2.2.4. Phenyl-substituted alkyne (ꢁ)-9. From 338 mg
(1.50 mmol) of terminal alkyne (ꢁ)-8, and after chromatography
of the residue using hexanes/ethyl acetate (1:1) as eluent gave
the phenylprop-2-ynyl dioxolane (ꢁ)-9 (261 mg, 58%) as a yel-
Few crystals of hydroxylamine hydrochloride, a 70% EtNH2
(0.25 mL) aqueous solution, and CuCl (0.006 mmol, 0.002 equiv)
were sequentially added at room temperature to a solution of the
alkynyl 2-azetidinone (þ)-7a (0.36 mmol) in methanol (1.8 mL).
Then, phenylacetylene (0.36 mmol) in CH2Cl2 (5 mL) was added to
the above acetylide suspension cooled at 0 ꢀC. More crystals of
hydroxylamine hydrochloride were added throughout the reaction
as necessary to prevent the solution from turning blue or green. The
reaction mixture was stirred until disappearance (TLC) of the
starting materials. The products were extracted with ethyl acetate
(3ꢂ5 mL), dried over MgSO4, and concentrated under reduced
pressure. Purification by column chromatography eluting with
ethyl acetate/hexanes (1/3) to give 118 mg (97%) of analytically pure
low solid. Mp 144e142 ꢀC. [
a
]
ꢁ4.3 (c 0.9, CHCl3). 1H NMR
D
(300 MHz, CDCl3, 25 ꢀC)
d 7.33 (m, 2H), 7.22 (m, 3H), 4.85 (m,
2H), 4.53 and 4.03 (d, J¼17.5 Hz, each 1H), 4.36 (td, J¼6.9, 4.5 Hz,
1H), 4.13 (dd, J¼9.0, 6.9 Hz, 1H), 3.85 (m, 2H), 1.42 and 1.28 (s,
each 3H). 13C NMR (75 MHz, CDCl3, 25 ꢀC)
d 169.4, 131.6, 128.5,
128.2, 122.2, 109.9, 84.2, 81.7, 75.7, 66.5, 60.2, 31.3, 26.7, 25.0. IR
(CHCl3)
n
1742, 2224 cmꢁ1. HRMS (ESI): calcd for [C17H19NO4]þ
301.1314, found 301.1310.
5.3. Procedure for the preparation of methyl-substituted
alkyne (D)-4e
1,3-diyne-
b-lactam (þ)-4d as a pale yellow oil.
A solution of the NH-
b
-lactam (þ)-(3R,4S)-4-[(S)-2,2-dimethyl-
5.5.1. 1,3-Diyne-
b
-lactam (þ)-4d. [
a
]
D þ0.78 (c 0.2, CHCl3). 1H NMR
1,3-dioxolan-4-yl]-3-methoxyazetidin-2-one34 (179 mg, 0.89 mmol)
in THF (2 mL) was slowly added to a suspension of sodium hydride
(38 mg, 1.98 mmol) in the same solvent (10 mL) at 0 ꢀC. After 1 h
stirring at room temperature, the solution was cooled at 0 ꢀC and
1-bromobut-2-yne (131 mg, 0.99 mmol) was added. The reactionwas
(300 MHz, CDCl3, 25 ꢀC)
d 7.49 (m, 2H), 7.35 (m, 3H), 4.54 and 4.06
(d, J¼18.0 Hz, each 1H), 4.49 (d, J¼5.1 Hz, 1H), 4.33 (m, 1H), 4.13 (dd,
J¼9.0, 6.6 Hz, 1H), 3.86 and 3.72 (dd, J¼9.0, 5.1 Hz, each 1H), 3.55 (s,
3H), 1.52 and 1.37 (s, each 3H). 13C NMR (75 MHz, CDCl3, 25 ꢀC)
d
166.7, 132.6, 129.3, 128.4, 121.3, 109.8, 83.2, 77.3, 76.6, 75.9, 73.3,

10756
B. Alcaide et al. / Tetrahedron 68 (2012) 10748e10760
68.7, 66.6, 59.5, 59.2, 31.4, 26.9, 25.2. IR (CHCl3)
n
1743, 2195 cmꢁ1
.
31.4, 3.3. IR (CHCl3) n
3454, 1745, 2215 cmꢁ1. HRMS (ESI): calcd for
HRMS (ESI): calcd for [C20H21NO4]þ 339.1471, found 339.1466.
[C10H15NO4]þ 213.1001, found 213.1009.
5.6. General procedure for the preparation of 2-azetidinone-
tethered alkynic diols 1aee, 2a, 2b, and 3aed
5.6.6. Alkynic diol (þ)-2a. From 266 mg (0.80 mmol) of dioxolane
(þ)-5a, diol (þ)-2a (233 mg, quantitative yield) was obtained as
yellow oil. [
25 ꢀC)
a
]
þ1.0 (c 0.7, CHCl3). 1H NMR (300 MHz, CDCl3,
D
To
a
solution of the corresponding acetonide
b
-lactam
d
7.37 and 6.80 (d, J¼9.0 Hz, each 2H), 4.89 (d, J¼5.4 Hz,
(10 mmol) in THF/water (1:1, 200 mL) was added solid p-TsOH.H2O
(12 mmol) in a single portion. The resulting clear solution was
heated under reflux for 2 h. The reaction mixture was allowed to
cool to room temperature, and then was neutralized with solid
NaHCO3. The mixture was extracted with ethyl acetate (3ꢂ40 mL),
the organic layer was dried (MgSO4) and the solvent was removed
under reduced pressure to give diols 1e3. Further purification was
not necessary. Spectroscopic and analytical data for some repre-
sentative forms of 1e3 follow.
1H), 4.42 (m, 2H), 4.35 (m, 1H), 4.08 (m, 2H), 3.72 (s, 3H), 3.60 (d,
J¼5.6 Hz, 1H), 3.34 (br s, 2H), 2.57 (t, J¼2.5 Hz, 1H). 13C NMR
(75 MHz, CDCl3, 25 ꢀC)
d 164.8, 156.6, 130.6, 119.9, 114.0, 79.5,
78.3, 76.4, 76.3, 71.3, 63.4, 58.9, 55.3. IR (CHCl3)
n 3442, 1744,
2172 cmꢁ1. HRMS (ESI): calcd for [C15H17NO5]þ 291.1107, found
291.1110.
5.6.7. Alkynic diol (þ)-2b. From 162 mg (0.40 mmol) of dioxolane
(þ)-5b, diol (þ)-2b (147 mg, quantitative yield) was obtained as
colorless oil. [
25 ꢀC)
a
]
þ14.9 (c 0.9, CHCl3). 1H NMR (300 MHz, CDCl3,
D
5.6.1. Alkynic diol (þ)-1a. From 220 mg (0.92 mmol) of dioxolane
(þ)-4a, diol (þ)-1a (183 mg, quantitative yield) was obtained as
d
7.39 (m, 7H), 6.82 (d, J¼9.0 Hz, 2H), 4.99 (d, J¼5.4 Hz, 1H),
4.66 (d, J¼2.0 Hz, 2H), 4.39 (t, J¼4.9 Hz, 1H), 4.17 (m, 1H), 3.73 (s,
a yellow oil. [
a
]
þ0.2 (c 1.0, CHCl3). 1H NMR (300 MHz, CDCl3,
3H), 3.65 (d, J¼5.9 Hz, 2H), 2.96 (br s, 2H). 13C NMR (75 MHz, CDCl3,
D
25 ꢀC)
d
4.52 (d, J¼4.9 Hz, 1H), 4.36 (dd, J¼17.5, 2.5 Hz, 1H), 4.00 (m,
25 ꢀC)
d 164.9, 156.6, 131.7, 130.7, 128.8, 128.3, 121.8, 120.0, 114.1,
2H), 3.92 (m, 2H), 3.70 (m, 2H), 3.60 (s, 3H), 3.07 and 2.59 (br s, each
87.8, 83.4, 79.7, 71.4, 63.5, 59.8, 58.4, 55.3. IR (CHCl3) n 3435, 1745,
1H), 2.31 (t, J¼2.4 Hz, 1H). 13C NMR (75 MHz, CDCl3, 25 ꢀC)
d
167.0,
2175 cmꢁ1. HRMS (ESI): calcd for [C21H21NO5]þ 367.1420, found
367.1414.
83.3, 72.8, 70.8, 63.9, 59.5, 58.1, 31.0. IR (CHCl3)
n 3450, 1744,
2180 cmꢁ1. HRMS (ESI): calcd for [C9H13NO4]þ 199.0845, found
199.0851.
5.6.8. Alkynic diol (þ)-2c. From 120 mg (0.35 mmol) of dioxolane
(þ)-5c, diol (þ)-2c (107 mg, quantitative yield) was obtained as
5.6.2. Alkynic diol (ꢁ)-1b. From 199 mg (0.59 mmol) of dioxolane
(þ)-4b, diol (ꢁ)-1b (162 mg, quantitative yield) was obtained as
colorless oil. [
a
]
þ36.9 (c 0.1, CHCl3). 1H NMR (300 MHz, CDCl3,
D
25 ꢀC)
d
7.38 and 6.83 (d, J¼9.0 Hz, each 2H), 4.96 (d, J¼5.4 Hz, 1H),
colorless solid. Mp 102e104 ꢀC. [
a
]
ꢁ0.4 (c 0.6, CHCl3). 1H NMR
4.42 (m, 3H), 4.18 (m, 1H), 3.76 (s, 3H), 3.75 (m, 1H), 3.64 (d,
D
(300 MHz, CDCl3, 25 ꢀC)
d
7.34 (m, 5H), 4.55 and 4.14 (d, J¼18.0 Hz,
J¼6.1 Hz, 1H), 3.12 and 2.68 (br s, each 1H), 1.87 (t, J¼2.3 Hz, 1H). 13C
each 1H), 4.49 (d, J¼4.9 Hz,1H), 4.01 (m,1H), 3.96 (dd, J¼9.5, 4.6 Hz,
NMR (75 MHz, CDCl3, 25 ꢀC)
d 165.0, 156.6, 130.7, 119.9, 114.1, 84.6,
1H), 3.71 (m, 2H), 3.57 (s, 3H), 3.21 (br s, 2H). 13C NMR (75 MHz,
79.5, 73.7, 71.3, 63.5, 59.7, 58.3, 55.4, 3.6. IR (CHCl3) n 3435, 1745,
CDCl3, 25 ꢀC)
d
167.1, 131.7, 128.6, 128.3, 122.0, 84.5, 83.3, 81.9, 70.9,
2175 cmꢁ1. HRMS (ESI): calcd for [C16H19NO5]þ 305.1263, found
305.1257.
63.9, 59.4, 58.0, 31.8. IR (CHCl3)
n
3445, 1742, 2185 cmꢁ1. HRMS
(ESI): calcd for [C15H17NO4]þ 275.1158, found 275.1162.
5.6.9. Alkynic diol (ꢁ)-3a. From 56 mg (0.21 mmol) of dioxolane
(þ)-6a, diol (ꢁ)-3a (47 mg, quantitative yield) was obtained as
5.6.3. Alkynic diol (þ)-1c. From 141 mg (0.44 mmol) of dioxolane
(þ)-4c, diol (þ)-1c (124 mg, quantitative yield) was obtained as
yellow oil. [
25 ꢀC)
a
]
ꢁ5.5 (c 0.2, CHCl3). 1H NMR (300 MHz, CDCl3,
D
yellow oil. [
a
]
D þ2.3 (c 0.1, CHCl3). 1H NMR (300 MHz, CDCl3, 25 ꢀC)
d
4.85 (d, J¼5.0 Hz, 1H), 4.44 (ddd, J¼23.2, 16.0, 2.3 Hz,
d
7.22 (dd, J¼5.1, 1.0 Hz, 1H), 7.18 (dd, J¼3.7, 1.0 Hz, 1H), 6.93 (dd,
2H), 4.34 (dd, J¼13.0, 2.5 Hz, 1H), 4.05 (m, 1H), 3.97 (m, 2H), 3.78
(dd, J¼11.5, 3.7 Hz, 1H), 3.67 (dd, J¼11.5, 6.1 Hz, 1H), 3.13 and 2.75
(br s, each 1H), 2.55 (t, J¼2.3 Hz, 1H), 2.32 (t, J¼2.5 Hz, 1H). 13C
J¼5.1, 3.7 Hz, 1H), 4.57 and 4.15 (d, J¼17.8 Hz, each 1H), 4.49 (d,
J¼4.9 Hz, 1H), 3.99 (m, 1H), 3.92 (t, J¼4.9 Hz, 1H), 3.69 (m, 2H), 3.56
(s, 3H), 3.20 (br s, 2H). 13C NMR (75 MHz, CDCl3, 25 ꢀC)
d
167.1,132.5,
NMR (75 MHz, CDCl3, 25 ꢀC)
d 166.6, 80.4, 78.2, 76.8, 76.2, 72.9,
127.4, 126.9, 121.9, 86.0, 83.3, 77.7, 71.0, 63.9, 59.4, 58.0, 31.9. IR
(CHCl3) HRMS (ESI): calcd for
3440, 1744, 2180 cmꢁ1
[C13H15NO4S]þ 281.0722, found 281.0717.
70.9, 63.8, 58.8, 58.2, 30.4, 31.2. IR (CHCl3) n 3440, 3315,
n
.
1745 cmꢁ1. HRMS (ESI): calcd for [C11H13NO4]þ 223.0845, found
223.0852.
5.6.4. Alkynic diol (ꢁ)-1d. From 55 mg (0.16 mmol) of dioxolane
(þ)-4d, diol (ꢁ)-1d (48 mg, quantitative yield) was obtained as
5.6.10. Alkynic diol (ꢁ)-3b. From 32 mg (0.078 mmol) of dioxolane
(þ)-6b, diol (ꢁ)-3b (29 mg, quantitative yield) was obtained as
yellow oil. [
a
]
D ꢁ1.9 (c 1.1, CHCl3). 1H NMR (300 MHz, CDCl3, 25 ꢀC)
colorless oil. [
25 ꢀC)
a
]
D
ꢁ1.2 (c 1.4, CHCl3). 1H NMR (300 MHz, CDCl3,
d
7.50 (m, 2H), 7.34 (m, 3H), 4.57 (d, J¼5.1 Hz, 1H), 4.55 and 4.12 (d,
d
7.45 (m, 4H), 7.33 (m, 6H), 5.00 (d, J¼5.1 Hz, 1H), 4.73 and
J¼12.2 Hz, each 1H), 4.05 (m, 1H), 3.98 (m, 1H), 3.82 (m, 1H), 3.73
4.66 (d, J¼16.0 Hz, each 1H), 4.54 and 4.20 (d, J¼17.0 Hz, each 1H),
(dd, J¼6.0, 4.7 Hz, 1H), 3.63 (s, 3H), 2.89 (br s, 2H). 13C NMR
4.18 (m, 1H), 4.05 (t, J¼4.6 Hz, 1H), 3.83 (m, 1H), 2.12 (br s, 1H). 13C
(75 MHz, CDCl3, 25 ꢀC)
d
166.8, 132.6, 129.5, 128.4, 83.6, 77.7, 75.5,
NMR (75 MHz, CDCl3, 25 ꢀC)
d 166.6, 131.9, 131.8, 128.9, 128.8, 128.4,
73.1, 70.6, 69.2, 64.0, 59.6, 58.3, 32.0. IR (CHCl3)
n
3450, 1743,
128.3, 122.0, 121.9, 87.9, 84.8, 83.4, 81.8, 80.7, 70.7, 64.0, 59.8, 58.4,
2175 cmꢁ1. HRMS (ESI): calcd for [C17H17NO4]þ 299.1158, found
299.1166.
32.0. IR (CHCl3) n
3434, 2190, 1742 cmꢁ1. HRMS (ESI): calcd for
[C23H21NO4]þ 375.1471, found 375.1468.
5.6.5. Alkynic diol (þ)-1e. From 66 mg (0.16 mmol) of dioxolane
(þ)-4e, diol (þ)-1e (55 mg, quantitative yield) was obtained as
5.6.11. Alkynic diol (ꢁ)-3c. From 56 mg (0.17 mmol) of dioxolane
(þ)-6c, diol (ꢁ)-3c (51 mg, quantitative yield) was obtained as
colorless oil. [
25 ꢀC)
a
]
D
þ4.6 (c 0.7, CHCl3). 1H NMR (300 MHz, CDCl3,
colorless oil; [
a
]
ꢁ0.4 (c 4.3, CHCl3). 1H NMR (300 MHz, CDCl3,
D
d
4.48 (d, J¼5.1 Hz,1H), 4.25 and 3.87 (dq, J¼17.4, 2.3 Hz, each
25 ꢀC)
d
7.44 (m, 2H), 7.31 (m, 3H), 4.94 (d, J¼5.0 Hz, 1H), 4.69 and
1H), 3.98 (m, 1H), 3.88 (t, J¼5.0 Hz, 1H), 3.68 (m, 2H), 3.57 (s, 3H),
4.62 (d, J¼16.0 Hz, each 1H), 4.37 and 3.97 (dd, J¼17.7, 2.5 Hz, each
1H), 4.11 (m, 1H), 3.96 (t, J¼5.0 Hz, 1H), 3.81 (dd, J¼11.4, 3.8 Hz, 1H),
3.71 (dd, J¼11.4, 6.2 Hz,1H), 2.74 (br s, 2H), 2.32 (t, J¼2.5 Hz,1H). 13C
3.16 and 2.78 (br s, each 1H), 1.79 (t, J¼2.4 Hz, 1H). 13C NMR
(75 MHz, CDCl3, 25 ꢀC)
d 167.0, 83.2, 80.7, 72.0, 71.0, 63.9, 59.4, 58.0,

B. Alcaide et al. / Tetrahedron 68 (2012) 10748e10760
10757
NMR (75 MHz, CDCl3, 25 ꢀC)
d
166.8, 131.8, 128.9, 128.4, 121.9, 87.8,
3.7 Hz, 1H), 4.72 (d, J¼5.1 Hz, 1H), 4.55 and 3.77 (d, J¼4.7 Hz, each
1H), 4.19 (dd, J¼8.0, 5.1 Hz, 1H), 4.08 (m, 1H), 3.89 (ddd, J¼14.4,
5.4, 1.2 Hz, 1H), 3.61 (s, 3H), 3.09 (ddd, J¼14.5, 12.2, 3.9 Hz, 1H),
2.48 (ddd, J¼14.5, 12.2, 5.4 Hz, 1H), 2.22 (dd, J¼14.5, 2.8 Hz, 1H).
83.4, 80.5, 77.2, 76.8, 72.9, 70.8, 63.9, 59.7, 58.3, 31.1. IR (CHCl3)
n
3442, 3300, 2192, 1740 cmꢁ1. HRMS (ESI): calcd for [C17H17NO4]þ
299.1158, found 299.1162.
13C NMR (75 MHz, CDCl3, 25 ꢀC)
d 168.1, 146.0, 126.9, 125.2, 124.2,
5.6.12. Alkynic diol (ꢁ)-3d. From 30 mg (0.088 mmol) of dioxolane
(þ)-6d, diol (ꢁ)-3d (26 mg, quantitative yield) was obtained as
109.8, 83.4, 72.5, 71.3, 62.7, 59.3, 37.3, 36.3. IR (CHCl3) n 1746, 1192,
1045 cmꢁ1. HRMS (ESI): calcd for [C13H15NO4SþNa]þ 304.0619,
colorless oil. [
a
]
ꢁ1.2 (c 1.3, CHCl3). 1H NMR (300 MHz, CDCl3,
found 304.0614.
D
25 ꢀC)
d
7.43 (m, 2H), 7.32 (m, 3H), 4.90 (d, J¼5.0 Hz, 1H), 4.57 and
4.19 (d, J¼17.7 Hz, each 1H), 4.43 and 4.50 (dd, J¼16.0, 2.3 Hz, each
1H), 4.12 (m, 1H), 4.03 (t, J¼5.0 Hz, 1H), 3.83 (dd, J¼11.4, 4.0 Hz, 1H),
3.77 (dd, J¼11.4, 6.3 Hz, 1H), 2.54 (t, J¼2.3 Hz, 1H), 2.18 (br s, 2H). 13C
5.7.4. Tricyclic acetal (þ)-12c. From 104 mg (0.31 mmol) of alky-
nyldioxolane (þ)-4d, and after chromatography of the residue
using hexanes/ethyl acetate (1:2) as eluent gave the acetal
NMR (75 MHz, CDCl3, 25 ꢀC)
d
166.4, 131.8, 128.8, 128.4, 122.0, 84.7,
(þ)-12c (48 mg, 52%) as a pale yellow oil. [
a
]
D þ4.1 (c 1.0, CHCl3).
81.8, 80.6, 78.2, 76.2, 70.7, 64.0, 58.9, 58.2, 32.0. IR (CHCl3)
3294, 2190, 1743 cmꢁ1 HRMS (ESI): calcd for [C17H17NO4]þ
299.1158, found 299.1152.
n
3450,
1H NMR (300 MHz, CDCl3, 25 ꢀC)
d
7.45 (m, 2H), 7.33 (m, 3H), 4.71
.
(d, J¼5.1 Hz, 1H), 4.54 and 3.75 (d, J¼4.5 Hz, each 1H), 4.28 (dd,
J¼8.1, 5.1 Hz, 1H), 4.09 (d, J¼8.1 Hz, 1H), 3.85 (dd, J¼14.5, 5.2 Hz,
1H), 3.63 (s, 3H), 3.04 (ddd, J¼14.5, 12.2, 3.7 Hz, 1H), 2.48 (ddd,
J¼14.5, 12.3, 5.3 Hz, 1H), 2.20 (dd, J¼14.5, 2.5 Hz, 1H). 13C NMR
5.7. General procedure for the metal-catalyzed cyclization of
alkynyl dioxolanes 4L6 in the presence of water. Preparation
of bridged acetals 10, and 12e18
(75 MHz, CDCl3, 25 ꢀC)
d 168.0, 131.9, 128.9, 128.2, 121.5, 104.8,
86.4, 84.2, 83.5, 72.3, 71.6, 62.6, 59.3, 38.7, 35.9. IR (CHCl3)
n 1745,
1195, 1040 cmꢁ1
.
HRMS (ESI): calcd for [C17H17NO4þNa]þ
[AuClPPh3] (0.0093 mmol), AgOTf (0.0093 mmol), p-toluene-
sulfonic acid or FeCl3 (0.037 mmol), and water (0.37 mmol) were
sequentially added to a stirred solution of the corresponding
alkynyldioxolane 4e6 (0.37 mmol) in dichloromethane (0.37 mL).
The resulting mixture was heated in a sealed tube at 80 ꢀC until
disappearance of the starting material (TLC). The reaction was
allowed to cool to room temperature and filtered through a pack
of Celite. The filtrate was extracted with ethyl acetate (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 eluting with ethyl ace-
tate/hexanes mixtures gave analytically pure adducts 10, and
12e18.
322.1055, found 322.1050.
5.7.5. Tricyclic acetal (þ)-12d. From 90 mg (0.36 mmol) of alky-
nyldioxolane (þ)-4e, and after chromatography of the residue using
hexanes/ethyl acetate (1:2) as eluent gave the acetal (þ)-12d
(48 mg, 63%) as a colorless solid. Mp 132e134 ꢀC. [
a]
þ5.6 (c 3.3,
D
CHCl3). 1H NMR (300 MHz, CDCl3, 25 ꢀC)
d
4.55 (d, J¼5.4 Hz), 4.49 (d,
J¼4.6 Hz), 4.08 (dd, J¼7.9, 5.6 Hz, 1H), 3.95 (m, 1H), 3.74 (ddd,
J¼14.5, 5.3, 1.3 Hz,1H), 3.68 (d, J¼4.6 Hz,1H), 3.60 (s, 3H), 2.93 (ddd,
J¼14.5, 12.4, 3.6 Hz, 1H), 2.10 (ddd, J¼14.4, 12.4, 5.4 Hz, 1H), 1.75
(ddd, J¼14.2, 3.7, 1.3 Hz, 1H), 1.44 (s, 3H). 13C NMR (75 MHz, CDCl3,
25 ꢀC)
(CHCl3)
d 168.2, 111.9, 83.5, 71.9, 70.7, 62.7, 59.4, 37.2, 36.4, 26.5. IR
n
1746, 1192, 1042 cmꢁ1
. HRMS (ESI): calcd for
[C10H14NO4þH]þ 214.1079, found 214.1085.
5.7.1. Tricyclic acetal (ꢁ)-10. From 70 mg (0.29 mmol) of alky-
nyldioxolane (þ)-4a, and after chromatography of the residue
using hexanes/ethyl acetate (1:1) as eluent gave the acetal (ꢁ)-10
5.7.6. Tricyclic ketal (þ)-13c. From 107 mg (0.35 mmol) of alky-
nyldiol (þ)-2c, and after chromatography of the residue using
hexanes/ethyl acetate (2:1) as eluent gave the acetal (þ)-13c
(45 mg, 77%) as a colorless oil. [
(300 MHz, CDCl3, 25 ꢀC)
a
]
ꢁ1.3 (c 0.9, CHCl3). 1H NMR
D
d
4.79 and 4.66 (dd, J¼4.8, 1.2 Hz, each
(71 mg, 62%) as a colorless oil. [
(300 MHz, CDCl3, 25 ꢀC)
a
]
þ7.7 (c 0.6, CHCl3). 1H NMR
D
1H), 3.84 (m, 3H), 3.65 (s, 3H), 3.53 (m, 1H), 2.98 (dt, J¼12.9,
0.6 Hz, 1H), 1.51 (s, 3H). 13C NMR (75 MHz, CDCl3, 25 ꢀC)
173.8,
1750, 1192,
d
7.31 and 6.89 (d, J¼9.0 Hz, each 2H), 5.05
d
(m, 1H), 4.96 (d, J¼4.5 Hz, 1H), 4.50 (dd, J¼7.7, 3.7 Hz, 1H), 4.43 (t,
J¼4.7 Hz, 1H), 4.00 (m, 1H), 3.95 and 3.54 (d, J¼12.4 Hz, each 1H),
3.80 (s, 3H), 1.69 (q, J¼7.4 Hz, 2H), 0.97 (t, J¼7.4 Hz, 3H). 13C NMR
104.5, 83.9, 71.0, 69.1, 59.3, 55.4, 51.5, 22.9. IR (CHCl3)
n
1042 cmꢁ1. HRMS (ESI): calcd for [C9H13NO4þH]þ 200.0923, found
200.0927.
(75 MHz, CDCl3, 25 ꢀC)
d 161.7, 156.8, 130.0, 118.2, 114.7, 111.9, 83.6,
77.3, 73.0, 65.9, 59.3, 55.5, 26.7, 6.8. IR (CHCl3)
n 1744, 1192,
5.7.2. Tricyclic acetal (þ)-12a. From 49 mg (0.16 mmol) of alky-
nyldioxolane (þ)-4b, and after chromatography of the residue
using hexanes/ethyl acetate (1:1) as eluent gave the acetal
1041 cmꢁ1. HRMS (ESI): calcd for [C16H19NO5þH]þ 306.1341, found
306.1348.
(þ)-12a (26 mg, 63%) as a colorless solid. Mp 150e152 ꢀC. [
a
]
5.7.7. Tricyclic acetal (ꢁ)-15b. From 58 mg (0.17 mmol) of alky-
nyldioxolane (þ)-6b, and after chromatography of the residue using
hexanes/ethyl acetate (2:1) as eluent gave the acetal (ꢁ)-15b
D
þ5.0 (c 1.1, CHCl3). 1H NMR (300 MHz, CDCl3, 25 ꢀC)
d 7.44 (m,
5H), 4.66 and 4.57 (d, J¼4.8 Hz, each 1H), 4.09 (m, 1H), 4.01 (dd,
J¼8.1, 4.9 Hz, 1H), 3.87 (ddd, J¼14.4, 5.4, 1.5 Hz, 1H), 3.79 (d,
J¼4.6 Hz, 1H), 3.63 (s, 3H), 3.10 (ddd, J¼14.6, 12.0, 4.2 Hz, 1H), 2.34
(ddd, J¼14.4, 12.2, 5.4 Hz, 1H), 1.94 (ddd, J¼14.4, 3.9, 1.0 Hz, 1H).
(32 mg, 63%) as a pale yellow oil. [
a]
ꢁ1.8 (c 1.3, CHCl3). 1H NMR
D
(300 MHz, CDCl3, 25 ꢀC)
d
7.44 (m, 2H), 7.35 (m, 3H), 5.08 (dd, J¼4.5,
1.2 Hz, 1H), 4.98 (d, J¼4.2 Hz, 1H), 4.77 and 4.66 (d, J¼16.1 Hz, each
13C NMR (75 MHz, CDCl3, 25 ꢀC)
d 168.2, 142.5, 128.2, 128.1, 124.7,
1H), 3.81 (m, 3H), 3.60 (d, J¼4.5 Hz, 1H), 2.99 (dt, J¼13.0 Hz, 1H),
111.8, 83.5, 72.2, 71.2, 63.0, 59.2, 38.6, 36.5. IR (CHCl3)
n
1748, 1190,
1.52 (s, 3H). 13C NMR (75 MHz, CDCl3, 25 ꢀC)
d 173.5, 131.7, 128.9,
1044 cmꢁ1. HRMS (ESI): calcd for [C15H17NO4þH]þ 276.1236,
128.4, 122.0, 104.3, 87.6, 84.0, 81.3, 71.3, 69.0, 59.6, 56.0, 51.6, 22.9.
found 276.1232.
IR (CHCl3) n . HRMS (ESI): calcd for
1752, 1190, 1044 cmꢁ1
[C17H17NO4þH]þ 300.1236, found 300.1215.
5.7.3. Tricyclic acetal (þ)-12b. From 118 mg (0.37 mmol) of alky-
nyldioxolane (þ)-4c, and after chromatography of the residue
using hexanes/ethyl acetate (1:1) as eluent gave the acetal
5.7.8. Tricyclic acetal (þ)-17. From 85 mg (0.20 mmol) of alky-
nyldioxolane (þ)-6c, and after chromatography of the residue using
hexanes/ethyl acetate (2:1) as eluent gave the acetal (þ)-17 (35 mg,
(þ)-12b (60 mg, 58%) as a colorless solid. Mp 101e103 ꢀC. [
a]
D
þ5.4 (c 3.9, CHCl3). 1H NMR (300 MHz, CDCl3, 25 ꢀC)
d
7.23 (dd,
48%) as a colorless oil. [
a
]
þ0.3 (c 0.7, CHCl3). 1H NMR (300 MHz,
D
J¼5.0, 1.2 Hz, 1H), 7.09 (dd, J¼3.7, 1.2 Hz, 1H), 6.95 (dd, J¼5.0,
CDCl3, 25 ꢀC)
d 8.12 (m, 1H), 7.51 (m, 4H), 7.32 (m, 5H), 5.01 (d,

10758
B. Alcaide et al. / Tetrahedron 68 (2012) 10748e10760
J¼4.5 Hz, 1H), 4.89 (d, J¼4.7 Hz, 1H), 4.77 and 4.66 (d, J¼16.1 Hz,
each 1H), 4.03 (m, 2H), 3.91 and 3.13 (m, each 1H), 3.88 (d, J¼4.5 Hz,
1H), 2.37 (m, 1H), 1.96 (dd, J¼14.3, 2.6 Hz, 1H). 13C NMR (75 MHz,
1040 cmꢁ1. HRMS (ESI): calcd for [C21H21NO5þNa]þ 390.1317,
found 390.1311.
CDCl3, 25 ꢀC)
d 168.0, 142.5, 131.7, 130.2, 128.8, 128.5, 128.4, 128.3,
5.10. Metal/acid co-catalyzed cyclization of bis(alkynyl)
dioxolane (D)-6a in the presence of water. Preparation of
bridged acetals (L)-14, (L)-15a, and (D)-16a
128.2, 128.1, 111.8, 87.4, 84.3, 81.0, 72.5, 71.2, 63.5, 59.6, 38.6, 36.7. IR
(CHCl3)
n
1746, 1191, 1038 cmꢁ1. HRMS (ESI): calcd for [C23H21NO4]þ
375.1471, found 375.1457.
From 65 mg (0.25 mmol) of bis(alkynyl)dioxolane (þ)-6a, and
after chromatography of the residue using hexanes/ethyl acetate
(2:1) as eluent, 16 mg (29%) of the less polar compound (ꢁ)-15a,
22 mg (36%) of compound (ꢁ)-14, and 16 mg (27%) of the more
polar compound (þ)-16a were obtained.
5.8. Metal/acid co-catalyzed cyclization of alkynyldioxolane
(D)-4a in the absence of water. Preparation of bridged acetal
(L)-10 and ketone (D)-11
From 70 mg (0.29 mmol) of alkynyldioxolane (þ)-4a, and after
chromatography of the residue using hexanes/ethyl acetate (1:1) as
eluent, 18 mg (31%) of the less polar compound (ꢁ)-10 and 20 mg
(27%) of the more polar compound (þ)-11 were obtained.
5.10.1. Tricyclic acetal (ꢁ)-14. Pale yellow oil. [
a
]
ꢁ0.4 (c 0.7,
D
CHCl3). 1H NMR (300 MHz, CDCl3, 25 ꢀC)
d
4.99 (m, 1H), 4.79 (dd,
J¼4.5, 1.2 Hz, 1H), 4.60 and 4.42 (d, J¼17.7 Hz, each 1H), 3.89 (m,
2H), 3.80 and 2.99 (d, J¼13.0 Hz, each 1H), 3.60 (d, J¼4.7 Hz, 1H),
5.8.1. Ketone (þ)-11. Yellow oil. [
a
]
þ8.5 (c 0.8, CHCl3). 1H NMR
2.16 (s, 3H), 1.51 (s, 3H). 13C NMR (75 MHz, CDCl3, 25 ꢀC)
d 205.3,
D
(300 MHz, CDCl3, 25 ꢀC)
d
4.58 (d, J¼5.1 Hz, 1H), 4.30 (m, 2H), 4.09
173.3, 104.4, 82.9, 77.2, 71.2, 69.1, 56.0, 51.6, 26.1, 23.0. IR (CHCl3) n
(m, 2H), 3.85 (dd, J¼9.3, 5.1 Hz, 1H), 3.65 (m, 1H), 3.55 (s, 3H), 2.15
1747, 1710, 1195, 1044 cmꢁ1. HRMS (ESI): calcd for [C11H15NO5þH]þ
(s, 3H), 1.36 and 1.31 (s, each 3H). 13C NMR (75 MHz, CDCl3, 25 ꢀC)
242.1028, found 242.1023.
d
201.6, 167.9, 109.5, 83.3, 76.7, 66.6, 60.6, 59.2, 50.4, 27.2, 26.8, 25.1.
IR (CHCl3)
n
1743, 1715 cmꢁ1. HRMS (ESI): calcd for [C12H19NO5]þ
5.10.2. Tricyclic acetal (ꢁ)-15a. Colorless oil. [
CHCl3). 1H NMR (300 MHz, CDCl3, 25 ꢀC)
a
]
ꢁ1.2 (c 0.5,
D
257.1263, found 257.1259.
d
5.00 (dd, J¼4.5, 1.0 Hz,
1H), 4.90 (d, J¼4.1 Hz, 1H), 4.56 and 4.46 (dd, J¼16.1, 2.5 Hz, each
1H), 3.85 (m, 2H), 3.81 and 2.99 (d, J¼13.0 Hz, each 1H), 3.58 (d,
J¼4.5 Hz, 1H), 2.51 (t, J¼2.3 Hz, 1H), 1.51 (s, 3H). 13C NMR (75 MHz,
5.9. General procedure for the metal/acid co-catalyzed
cyclization of alkynyldiols 1e3. Preparation of bridged acetals
10, and 12e18
CDCl3, 25 ꢀC)
d 173.3, 104.3, 81.1, 78.7, 75.8, 71.2, 69.0, 58.7, 55.8,
51.6, 22.9. IR (CHCl3)
n
3315, 1745, 1192, 1045 cmꢁ1. HRMS (ESI):
calcd for [C11H13NO4þH]þ 224.0923, found 224.0919.
[AuClPPh3] (0.0093 mmol), AgOTf (0.0093 mmol), and p-tol-
uenesulfonic acid (0.037 mmol) were sequentially added to
5.10.3. Tricyclic acetal (þ)-16a. Colorless solid. Mp 150e152 ꢀC.
a
stirred solution of the corresponding alkynyldiols 1e3
[a
]
D þ6.6 (c 0.9, CHCl3). 1H NMR (300 MHz, CDCl3, 25 ꢀC)
d 4.91 (d,
(0.37 mmol) in dichloromethane (0.37 mL). The resulting mixture
was stirred at room temperature until disappearance of the
starting material (TLC), before being filtered through a pack of
Celite. The filtrate was extracted with ethyl acetate (3ꢂ5 mL),
and the combined extracts were washed twice with brine. The
organic layer was dried (MgSO4) and concentrated under re-
duced pressure. Chromatography of the residue eluting with
ethyl acetate/hexanes mixtures gave analytically pure adducts
10, and 12e18.
J¼4.4 Hz, 1H), 4.67 (m, 1H), 4.32 and 3.91 (d, J¼18.8 Hz, each 1H),
4.23 (m, 1H), 4.06 (t, J¼4.4 Hz, 1H), 3.89 and 3.47 (d, J¼12.5 Hz, each
1H), 2.15 (s, 3H), 1.37 (s, 3H). 13C NMR (75 MHz, CDCl3, 25 ꢀC)
d
201.5, 165.6, 110.0, 84.7, 78.1, 74.1, 66.8, 61.4, 50.8, 27.3, 20.6. IR
(CHCl3)
n
1747, 1712, 1192, 1042 cmꢁ1. HRMS (ESI): calcd for
[C11H15NO5]þ 241.0950, found 241.0937.
5.11. Metal/acid co-catalyzed cyclization of bis(alkynyl)
dioxolane (D)-6d in the presence of water. Preparation of
bridged acetals (D)-16b and (D)-18
5.9.1. Tricyclic acetal (þ)-13a. From 61 mg (0.21 mmol) of alky-
nyldiol (þ)-2a, and after chromatography of the residue using
hexanes/ethyl acetate (1:1) as eluent gave the acetal (þ)-13a
From 32 mg (0.096 mmol) of bis(alkynyl)dioxolane (þ)-6d, and
after chromatography of the residue using hexanes/ethyl acetate
(1:1) as eluent, 11 mg (37%) of the less polar compound (þ)-18 and
16 mg (52%) of the more polar compound (þ)-16b were obtained.
(40 mg, 63%) as a yellow solid. Mp 128e130 ꢀC. [
a]
þ13.0 (c 0.9,
D
CHCl3). 1H NMR (300 MHz, CDCl3, 25 ꢀC)
d 7.31 and 6.89 (d,
J¼9.0 Hz, each 2H), 5.04 (m, 1H), 4.95 (d, J¼4.4 Hz, 1H), 4.51 (dd,
J¼7.6, 3.7 Hz, 1H), 4.42 (t, J¼4.6 Hz, 1H), 4.03 (m, 1H), 3.94 (d,
J¼12.5 Hz,1H), 3.80 (s, 3H), 3.54 (dd, J¼12.4, 0.7 Hz,1H),1.41 (s, 3H).
5.11.1. Tricyclic acetal (þ)-16b. Colorless solid. Mp 123e125 ꢀC. [
a]
D
13C NMR (75 MHz, CDCl3, 25 ꢀC)
d
161.6, 156.8, 130.5, 118.2, 114.7,
þ2.7 (c 1.5, CHCl3). 1H NMR (300 MHz, CDCl3, 25 ꢀC)
d 7.95 (m, 2H),
110.3, 83.5, 77.8, 73.0, 65.9, 59.3, 55.5, 20.5. IR (CHCl3)
n
1747, 1188,
7.62 (m, 1H), 7.54 (m, 2H), 4.92 (m, 1H), 4.23 (d, J¼4.4 Hz, 1H), 4.37
(dd, J¼7.5, 3.6 Hz, 1H), 4.01 (t, J¼4.4 Hz, 1H), 3.92 (dd, J¼16.4, 7.5 Hz,
1H), 3.84 and 3.43 (d, J¼12.6 Hz, each 1H), 3.63 (m, 2H), 3.30 (m,
1038 cmꢁ1. HRMS (ESI): calcd for [C15H17NO5þNa]þ 314.1004, found
314.0999.
2H), 1.36 (s, 3H). 13C NMR (75 MHz, CDCl3, 25 ꢀC)
d 197.5, 165.5,
5.9.2. Tricyclic acetal (þ)-13b. From 114 mg (0.31 mmol) of alky-
nyldiol (þ)-2b, and after chromatography of the residue using
hexanes/ethyl acetate (2:1) as eluent gave the acetal (þ)-13b
135.9, 133.8, 128.8, 128.0, 110.0, 84.1, 77.8, 73.6, 65.9, 61.0, 37.2, 36.3,
20.6. IR (CHCl3) n
1743, 1705, 1190, 1040 cmꢁ1. HRMS (ESI): calcd for
[C17H19NO5]þ 317.1263, found 317.1249.
(74 mg, 60%) as a colorless oil. [
(300 MHz, CDCl3, 25 ꢀC)
a
]
þ3.9 (c 1.4, CHCl3). 1H NMR
D
d
7.28 (m, 7H), 6.87 (d, J¼9.0 Hz, 2H),
5.11.2. Tricyclic acetal (þ)-18. Colorless solid. Mp 153e155 ꢀC. [
a]
D
5.00 (m, 1H), 4.90 (d, J¼4.6 Hz, 1H), 4.47 (dd, J¼7.6, 3.7 Hz, 1H),
4.40 (t, J¼4.6 Hz, 1H), 3.99 and 3.49 (d, J¼12.2 Hz, each 1H), 3.91
(m, 1H), 3.79 (s, 3H), 3.00 (d, J¼1.8 Hz, 2H). 13C NMR (75 MHz,
þ11.6 (c 0.8, CHCl3). 1H NMR (300 MHz, CDCl3, 25 ꢀC)
d 7.37 (m, 5H),
4.96 (m, 1H), 4.87 (d, J¼4.2 Hz, 1H), 4.63 (dd, J¼7.7, 3.6 Hz, 1H), 4.51
and 4.06 (d, J¼17.8 Hz, each 1H), 4.10 (m, 2H), 3.89 and 3.47 (d,
J¼12.6 Hz, each 1H), 1.37 (s, 3H). 13C NMR (75 MHz, CDCl3, 25 ꢀC)
CDCl3, 25 ꢀC)
d 161.6, 156.8, 134.7, 130.3, 128.8, 128.2, 118.1, 114.7,
111.0, 83.5, 77.2, 73.1, 65.7, 59.2, 55.5, 40.8. IR (CHCl3)
n
1745, 1190,
d 163.9, 131.6, 129.0, 128.5, 121.6, 110.2, 85.1, 84.7, 81.4, 77.8, 73.6,

B. Alcaide et al. / Tetrahedron 68 (2012) 10748e10760
10759
66.2, 60.1, 31.7, 20.6. IR (CHCl3) n
2225, 1745, 1190, 1042 cmꢁ1. HRMS
In; Banik, B. K., Ed. Topics in Heterocyclic Chemistry; Springer: Berlin-Heidel-
berg, 2010; Vol. 22, p 349.
4. It has been reported that b-lactams act to modulate the expression of gluta-
(ESI): calcd for [C17H17NO4þH]þ 300.1236, found 300.1230.
mate neurotransmitter transporters via gene activation. See: Rothstein, J. D.;
Patel, S.; Regan, M. R.; Haenggeli, C.; Huang, Y. H.; Bergles, D. E.; Jin, L.; Hoberg,
M. D.; Vidensky, S.; Chung, D. S.; Toan, S. V.; Bruijn, L. I.; Su, Z.-z.; Gupta, P.;
Fisher, P. B. Nature 2005, 433, 73.
5.12. Procedure for the metal/acid co-catalyzed cyclization of
alkynyldioxolane (D)-4b using D2O instead of H2O.
Preparation of fused acetal (D)-[D]-12a
5. For selected reviews on the synthetic utility of b-lactams, see: (a) Alcaide, B.;
Almendros, P. Chem. Rec. 2011, 11, doi:10.1002/tcr.201100011; (b) Alcaide, B;
Almendros, P.; Aragoncillo, C. Chem. Rev. 2007, 107, 4437; (c) Alcaide, B.; Al-
mendros, P. Curr. Med. Chem. 2004, 11, 1921; (d) Deshmukh, A. R. A. S.; Bhawal,
B. M.; Krishnaswamy, D.; Govande, V. V.; Shinkre, B. A.; Jayanthi, A. Curr. Med.
Chem. 2004, 11, 1889; (e) Alcaide, B.; Almendros, P. Synlett 2002, 381; (f) Pal-
omo, C.; Aizpurua, J. M.; Ganboa, I.; Oiarbide, M. Synlett 2001, 1813; (g) Alcaide,
B.; Almendros, P. Chem. Soc. Rev. 2001, 30, 226; (h) Alcaide, B.; Almendros, P.
Org. Prep. Proced. Int. 2001, 33, 315; (i) Ojima, I.; Delaloge, F. Chem. Soc. Rev. 1997,
26, 377; (j) Manhas, M. S.; Wagle, D. R.; Chiang, J.; Bose, A. K. Heterocycles 1988,
27, 1755.
6. (a) Milroy, L. G.; Zinzalla, G.; Prencipe, G.; Michel, P.; Ley, S. V.; Gunaratnam, M.;
Beltran, M.; Neidle, S. Angew. Chem., Int. Ed. 2007, 46, 2493; (b) Maimone, T. J.;
Baran, P. S. Nat. Chem. Biol. 2007, 3, 396; (c) Matsuzawa, M.; Kakeya, H.;
Yamaguchi, J.; Shoji, M.; Onose, R.; Osada, H.; Hayashi, Y. Chem.dAsian J. 2006,
1, 845; (d) Evans, D. A.; Rajapakse, H. A.; Chiu, A.; Stenkamp, D. Angew. Chem.,
Int. Ed. 2002, 41, 4573; (e) Araki, K.; Suenaga, K.; Sengoku, T.; Uemura, D. Tet-
rahedron 2002, 58, 1983; (f) Mitchell, S. S.; Rhodes, D.; Bushman, F. D.; Faulkner,
D. J. Org. Lett. 2000, 2, 1605; (g) Uemura, D.; Chou, T.; Haino, T.; Nagatsu, A.;
Fukuzawa, S.; Zheng, S.; Chen, H. J. Am. Chem. Soc. 1995, 117, 1155; (h) Wood, D.
L.; Browne, L. E.; Ewing, B.; Lindahl, K.; Bedard, W. D.; Tilden, P. E.; Mori, K.;
Pitman, G. B.; Hughes, P. R. Science 1976, 192, 896; (i) Ellory, J. C.; Tucker, E. M.
Nature 1969, 222, 477.
[AuClPPh3] (0.0063 mmol), AgOTf (0.0063 mmol), p-toluene-
sulfonic acid, and deuterium oxide (0.50 mmol) were sequentially
added to a stirred solution of the alkynyldioxolane (þ)-4b (78 mg,
0.25 mmol) in dichloromethane (0.25 mL). The resulting mixture
was heated in a sealed tube at 80 ꢀC for 3 h. The reaction was
allowed to cool to room temperature and filtered through a pack of
Celite. The filtrate was extracted with ethyl acetate (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 eluting with hexanes/ethyl acetate
(1:2) gave 51 mg (65%) of analytically pure adduct (D)-[D]-12a; as
a colorless solid. Mp 160e162 ꢀC. [
(300 MHz, CDCl3, 25 ꢀC)
a
]
þ7.9 (c 0.9, CHCl3). 1H NMR
D
d
7.57 (m, 2H), 7.32 (m, 3H), 4.67 (d,
J¼4.9 Hz, 1H), 4.57 (d, J¼4.7 Hz, 1H), 3.87 (ddd, J¼14.4, 5.4, 1.5 Hz,
1H), 3.79 (d, J¼4.6 Hz, 1H), 3.63 (s, 3H), 4.05 (m, 2H), 3.87 and 3.10
(d, J¼14.4 Hz, each 1H), 3.80 (d, J¼4.7 Hz, 1H), 3.64 (s, 3H). 13C NMR
7. (a) Acetylene Chemistry: Chemistry, Biology and Materials Science; Diederich, F.,
Stang, P. J., Tykwinski, R. R., Eds.; Wiley-VCH: Weinheim, 2005; (b) Bohlmann,
F.; Burkhart, F. T.; Zero, C. In Naturally Occurring Acetylenes; Academic: London
and New York, NY, 1973.
(75 MHz, CDCl3, 25 ꢀC)
d 167.7, 142.0, 127.7, 127.6, 124.3, 111.2, 83.0,
71.8, 70.8, 62.5, 58.8, 36.0 (m). IR (CHCl3)
n .
1749, 1190, 1045 cmꢁ1
HRMS (ESI): calcd for [C15H15D2NO4þNa]þ 300.1181, found
8. For reviews on the construction of heterocycles by alkyne p-activation, see: (a)
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Rudolph, M.; Hashmi, A. S. K. Chem. Commun. 2011, 47, 6536; (b) Krause, N.;
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Perez, A.; Sabater, M. J. Chem. Rev. 2011, 111, 1657; (f) Alcaide, B.; Almendros, P.;
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Support for this work by the DGI-MICINN (Projects CTQ2009-
ꢀ
09318 and CTQ2007-63266), Comunidad Autonoma de Madrid
(Project S2009/PPQ-1752) and SANTANDER-UCM (Project GR35/10)
are gratefully acknowledged. R.C. thanks the MEC for a predoctoral
grant.
€
9. For selected examples, see: (a) Wang, T.; Zhang, J. Chem.dEur. J. 2011, 17, 86; (b)
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Supplementary data
Schemes S1eS4, Figures S1eS3, Table S1 and Table S2, ORTEP
plot for compound 12a, computational data, as well as copies of the
1H NMR and 13C NMR spectra for all new compounds. Supple-
mentary data related to this article can be found online at
doi:10.1016/j.tet.2012.03.028.
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pounds 4 for the conversion into the corresponding diols 1 takes 2 h at reflux
temperature (THF/H2O) in our experiments in the laboratory (see Schemes
S1eS3 in the Supplementary data); which would imply energy barriers
above 20 kcal/mol based on the thermodynamic formulation of Transition State
Theory. Because, the reaction barrier from acetonides 4 to diols 1 is higher than
that of the reaction of acetonides 4 in Fig. 3, we think that it is reasonable to
rule out the pathway through the diol because the alkyne functionality of
compounds 4 may interact with the gold atom before the acetonide moiety was
converted into the corresponding 1,2-diol.
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ꢁ
(Mr¼275.30); monoclinic; space group¼P2(1); a¼11.3463(16) A, b¼5.
3
ꢁ
ꢀ
ꢁ
ꢁ
€
8344(8) A; c¼11.4061(16) A;
b
¼112.014(2) ; V¼700.02(17) A ; Z¼2;Dcalcd¼1.
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;
m
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