Gold/acid-cocatalyzed regiodivergent preparation of bridged ketals via direct bis-oxycyclization of alkynic acetonides

Article abstract of DOI:10.1002/adsc.201000124

The regioselective metal/acid co-catalyzed direct bis-oxycyclization of alkynyldioxolanes allows the efficient synthesis of optically pure biand tricyclic bridged acetal systems.

Full text of DOI:10.1002/adsc.201000124

COMMUNICATIONS
DOI: 10.1002/adsc.201000124
Gold/Acid-Cocatalyzed Regiodivergent Preparation of Bridged
Ketals via Direct Bis-Oxycyclization of Alkynic Acetonides
Benito Alcaide,a,* Pedro Almendros,b,* Rocꢀo Carrascosa,a and M. Rosario Torresc
a
Grupo de Lactamas y Heterociclos Bioactivos, Departamento de Quꢀmica Orgꢁnica I, Facultad de Quꢀmica, Unidad
Asociada al CSIC, Facultad de Quꢀmica, Universidad Complutense de Madrid, 28040 Madrid, Spain
Fax : (+34) 91-394-4103; e-mail: alcaideb@quim.ucm.es
Instituto de Quꢀmica Orgꢁnica General, Consejo Superior de Investigaciones Cientꢀficas, CSIC, Juan de la Cierva 3, 28006
b
Madrid, Spain
Fax : (+34) 91-564-4853; e-mail: Palmendros@iqog.csic.es
CAI Difracciꢂn de Rayos X, Facultad de Quꢀmica, Universidad Complutense de Madrid, 28040 Madrid, Spain
c
Received: February 16, 2010; Revised: April 12, 2010; Published online: May 7, 2010
In memory of our colleague and friend Josꢃ Manuel Concellꢂn.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000124.
Abstract: The regioselective metal/acid co-catalyzed
direct bis-oxycyclization of alkynyldioxolanes
allows the efficient synthesis of optically pure bi-
and tricyclic bridged acetal systems.
tion reactions. To screen the reactivity of the alkynyl-
dioxolane moiety, several metal salts were screened.
While AgOTf, FeCl3, and [PtCl2ACHTNUTRGNE(UGN CH2=CH2)]2 could
not catalyze the heterocyclization reaction alone or in
the presence of different additives, the catalytic
system AuCl3/PTSA gave the desired ketal 2a in a
low 30% yield. Fortunately, we found that under the
appropriate reactions conditions, a gold(I) salt along
with a Brønsted (or Lewis) acid could be an excellent
cooperative catalytic system for this purpose (Table 1,
entries 8 and 9).[5] The Lewis and Brønsted acid co-
Keywords: alkynes; gold; heterocycles; regioselec-
tivity; synthetic methods
Acetals are structural units which have been shown to catalysts, FeCl3 and PTSA, were effective, but the
be the major component of many biologically impor- former did not exhibit the wide applicability observed
tant natural products and functional molecules. Thus,
the synthesis of these heterocycles is of current inter-
est. The use of gold salts has gained a lot of attention
in the recent times because of their powerful soft
Lewis acidic nature.[1] In particular, activation of al-
kynes towards attack by oxygen nucleophiles such as
carbonyls, carboxylic acids, and alcohols, is an impor-
[2]
À
tant C O bond-forming reaction. Although many
efforts have been made in these fields, metal-cata-
lyzed heterocyclizations of alkynes bearing a dioxo-
lane ring as nucleophilic moiety have not been men-
tioned in the literature. Encouraged by our recent re-
sults in heterocyclic chemistry,[3] we thought that re-
gioselective metal-catalyzed direct bis-oxycyclization
of alkynyldioxolanes may occur by judicious choice of
the catalytic system. Herein, we report our findings in
this field.
The structures of alkynyldioxolanes 1 that we syn-
thesized and used for bis-oxycyclization are shown in
Figure 1.[4] Alkynyldioxolane 1a was chosen as a
Figure 1. Structures of alkynyldioxolanes 1a–k. PMP=4-
model substrate for metal-catalyzed cycloetherifica- MeOC6H4.
Adv. Synth. Catal. 2010, 352, 1277 – 1283
ꢄ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1277

Benito Alcaide et al.
COMMUNICATIONS
Table 1. Selective cyclo-ketalization reaction of alkynyldioxolane 1a under modified metal/Brønsted (or Lewis) acid-cocata-
lyzed conditions.[a]
Entry
Metal catalyst (mol%)
[PtCl2A(CH2=CH2)]2 (1)
AgOTf (5)
FeCl3 (10)
AuCl3 (2.5)
AuCl (2.5)
R
N
G
ACHTUNGTRENNUNG
Additive (mol%)
Time [h]
Acid
Conversion, yield [%]
1
2
3
4
5
6
7
8
9
G
G
TDMPP (2)
–
–
–
–
–
–
24
24
24
24
24
24
24
15
3
–
–
PTSA
–
–[b]
[b,c]
–
PTSA
PTSA
FeCl3
PTSA
FeCl3
PTSA
100, 30
100, 40
90, 35
95, 46
100, 55
100, 79
H2O (100)
H2O (100)
[a]
Yield of pure, isolated product with correct analytical and spectral data; conversion=1H NMR conversions.
Quantitative conversion to the corresponding uncyclized alkynyldiol was observed.
[b]
[c]
No methyl ketone formation was observed despite it has been recently reported the iron chloride-catalyzed hydration of
terminal alkynes.[14] TDMPP=tris(2,6-dimethoxyphenyl)phosphine, PTSA=p-toluenesulfonic acid.
in the case of p-toluenesulfonic acid. Adding a stoi-
ACHTUNGTREN[NGNU 4.2.1]nonanes exclusively. The results are shown in
chiometric amount of water into the reaction system Scheme 1. It was desirable to scale-up the procedure
did improve the yield of 2a. Treatment of alkynyldi- to obtain gram quantities of the ketal derivatives.
ACHTUNGTRENNUNGoxolane 1a with [AuClPPh3] (2.5 mol%)/AgOTf Nicely, it quickly became clear that scale-up was pos-
(2.5 mol%)/PTSA (10 mol%)/H2O (100 mol%) in di- sible. Thus, an isolated 75% yield of adduct 2a was
chloromethane at 808C on a sealed tube afforded the obtained when the reaction was carried out on a gram
best yield of the 6-exo/5-exo bis-oxycyclization to scale.
afford the corresponding bicyclic ketal as a single
regio- and diastereomer (Table 1).
Given the interest in b-lactams and aiming to
extend the methodology beyond bicyclic acetals, 2-
With these optimal conditions in hand, we applied azetidinone-tethered alkynyldioxolanes 1f–k were ex-
them to the precious metal-catalyzed bis-oxycycliza- plored as substrates.[6] Using the terminal alkyne 1f,
tion reaction of alkynyldioxolanes 1b–e. The synthetic the catalytic system AuCl3/PTSA gave the desired
power of the process can be best demonstrated by ap- ketal 2f accompanied by appreciable amounts of a
plication of phenyl-substituted alkynyldioxolane 1b to polar ketone, arising from alkyne hydration.[7] Again,
the preparation of bridged acetal 2b. By contrast, and the [AuClPPh3]/AgOTf/PTSA system demonstrated
to our delight, the exposure of methyl-substituted al- better activity. Interestingly, reaction times for com-
kynyl dioxolane 1c to these reactions conditions ex- plete conversion were similar to those for the simpler
clusively afforded the 7-endo/5-exo bis-oxycyclization alkynyldioxolanes 1a–e. Worthy of note, in contrast to
bridged acetal 2c with not even a trace of the corre- the precious metal/acid-cocatalyzed reaction of termi-
sponding 6-exo/5-exo adduct; thus indicating that the nal alkynyl dioxolane 1f which leads to the 6,8-
nature of the alkyne side chain is crucial to the regio- dioxabicycloACTHNUTRGENUG[N 3.2.1]octane derivative 2f (proximal
selectivity of the cyclization. At present, we have no adduct), the reactions of substituted at the terminal
explanation for this behaviour. The bis-cycloetherifi- end alkynyl dioxolanes 1g and 1h under identical con-
cation was also accomplished on increasing the dis- ditions gave the 7,9-dioxabicycloACTHNUTRGNEUGN[4.2.1]nonane deriva-
tance between the dioxolane group and the alkyne tives 2g and 2h (distal adducts) as the sole products
moiety, such as in the analogous homologue sub- (Scheme 2), through an exclusive 7-endo/5-exo bis-
strates 1d and 1e. The related bridged acetals 2d and oxycyclization by initial attack of the oxygen atom to
2e (proximal adducts) were formed as single isomers the external alkyne carbon. The competition between
in reasonable yields following the same regiochemical the initial 6-exo and 7-endo oxycyclizations is gained
pattern as for 1a and 1b. All the reactions were com- by the latter, in spite of the a priori fact that it should
plete in 3 h as monitored by TLC, providing be energetically more demanding. The structure and
trioxabicyclo[3.2.1]octanes
or
trioxabicyclo- stereochemistry of the tricyclic acetal 2g were deter-
1278
asc.wiley-vch.de
ꢄ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 1277 – 1283

Gold/Acid-Cocatalyzed Regiodivergent Preparation of Bridged Ketals
Scheme 1. Controlled precious metal/Brønsted acid-cocatalyzed preparation of bridged bicyclic acetals 2a–e. Reagents and
conditions: i) 2.5 mol% [AuClPPh3], 2.5 mol% AgOTf, 10 mol% PTSA, 100 mol% H2O, CH2Cl2, sealed tube, 808C, 2a: 3 h;
2b: 3 h, 2c: 2 h; 2d: 3 h; 2e: 3 h. PTSA=p-toluenesulfonic acid.
Scheme 2. Controlled precious metal/Brønsted acid-cocatalyzed preparation of bridged tricyclic acetals 2f–k. Reagents and
conditions: i) 2.5 mol% [AuClPPh3], 2.5 mol% AgOTf, 10 mol% PTSA, 100 mol% H2O, CH2Cl2, sealed tube, 808C, 2f: 2 h;
2g: 3 h; 2h: 2 h; 2i: 2 h; 2j: 3 h; 2k: 3 h. PMP=4-MeOC6H4, PTSA=p-toluenesulfonic acid.
mined by X-ray crystallography,[8] as it is shown in preted by considering the ring size of the intermedi-
Figure 2. Although we suspected that on the b-lactam ates (7-membered versus 8-membered rings). Proba-
series the regioselectivity for the phenyl- or methyl- bly, the combination of developing ring strain and the
substituted alkynyldioxolanes 1j and 1k would be the requirement to restrict rotations around flexible
same as for the previous set of experiments for substi- bonds in the fused 8,10-dioxabicycloACHTNUTRGNE[NUG 5.2.1]decane
tuted alkynyldioxolanes 1g and 1h, we found that in system ensures unfavourable enthalpic and entropic
this case bridged tricyclic acetals 2j and 2k (proximal contributions to DG, avoiding its formation.
adducts) were obtained as single regio- and diastereo-
The reaction may tentatively be classified as coop-
mers. Thus, by using a related alkynyldioxolane ho- erative concurrent catalysis, involving a catalytic
mologue (1j versus 1g or 1k versus 1h), the regioselec- action by the Au(I) salt on the alkynic site, and by the
tivity can be reversed, favouring the 7-exo/5-exo bis- Brønsted (or Lewis) acid on the activation of the
oxycyclization of the acetonide group towards the in- transient methylenic intermediate.[9] AgOTf cannot be
ternal alkyne carbon (proximal adduct) over the 8- considered as a cocatalyst because its action is gener-
endo/5-exo bis-oxycyclization towards the external ally assumed to be restricted to forming cationic gold
alkyne carbon (distal adduct). The exclusive forma- species by anion exchange.[10] A possible pathway for
tion of proximal adducts 2j and 2k would be inter- the gold/acid-cocatalyzed alkynyldioxolane cyclization
Adv. Synth. Catal. 2010, 352, 1277 – 1283
ꢄ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1279

Benito Alcaide et al.
COMMUNICATIONS
collaboration of the Brønsted (or Lewis) acid would
exhibit a benefitial influence.[5,9] Mechanistically, this
gold-catalyzed reaction might also proceed in a
tandem sequence involving as the first step the forma-
tion of the p-complex 3 through coordination of the
gold salt to the triple bond of alkynyldioxolanes
1.[11,12] As above in Scheme 3, species 3 evolves
through 6-exo alkoxyauration to intermediates 4,
which after sequential demetalation and acetonide hy-
drolysis lead to methylenic oxacycles 5, releasing the
gold catalyst into the first catalytic cycle. Next, meth-
ylenic oxacycles 5 enter the second catalytic cycle,
which is also gold-catalyzed, generating species 8 by
coordination of the alkene group with the metal, thus
enhancing the electrophilicity of the resulting enol
ether. Subsequent intramolecular nucleophilic attack
of the primary alcohol to the internal alkene position
would form the ate complex 9. Demetalation linked
Figure 2. X-ray diffraction analysis of tricyclic bridged acetal
2g.
may initially involve the formation of a p-complex 3 to proton transfer liberates adduct 2 with concomitant
through coordination of the gold salt to the triple regeneration of the gold catalyst, closing the second
bond of alkynyldioxolanes 1.[11] Next, 6-exo oxymeta- catalytic cycle (Scheme 4).
lation forms the zwitterionic enol vinylmetal species
In order to confirm the mechanistic proposals of
4. Intermediates 4 would evolve through demetalation Scheme 3 and Scheme 4, we performed in substrate
and acetonide hydrolysis forming methylenic oxacy- 1g both a control experiment as well as labeling stud-
cles 5 and releasing the metal catalyst into the first ies with deuterium oxide. A mechanistic experiment
catalytic cycle. Methylenic oxacycles 5 enter the was carried out, namely, the reaction of acetonide 1g
second catalytic cycle generating species 6 by proto- under gold catalysis in the absence of acid additive. In
nation of the alkene group, thus, enhancing the elec- this event, the reaction proceeded to afford the corre-
trophilicity of the resulting carbonyl carbon. Subse- sponding ketal 2g in just a slightly lower 58% yield.
quent intramolecular nucleophilic attack of the pri- Even more important, the gold catalyst alone did not
mary alcohol to the carbonylic-like position would produce an observable intermediate of type 5. This
form oxoniums 7. Deprotonation liberates adduct 2 would suggest that the acid is not necessarily needed
with concomitant regeneration of the acid catalyst, for the second step of the proposed catalytic cycle to
closing the second catalytic cycle (Scheme 3).
proceed, because this latter step may also be cata-
On the basis of the experimental results, an alterna- lyzed by gold. However, the comparative studies of
tive mechanism for the observed catalytic cyclo-ketal- ketal formation with addition of PTSA demonstrated
ization of alkynyldioxolanes to produce ketals could that the presence of the Brønsted acid gives higher
be proposed (Scheme 4). Accordingly, it is also possi- yields. On the basis of the above results, Scheme 4
ble that a catalytic action by the Au(I) salt, with the should be the more plausible reaction mechanism.
Scheme 3. Mechanistic explanation for the metal/acid-cocatalyzed controlled preparation of bridged ketals.
1280
asc.wiley-vch.de
ꢄ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 1277 – 1283

Gold/Acid-Cocatalyzed Regiodivergent Preparation of Bridged Ketals
Scheme 4. Mechanistic explanation for the gold-catalyzed controlled preparation of bridged ketals.
When alkynyldioxolane 1g was treated under cyclo-
In summary, a novel method was developed for the
ketalization conditions employing D2O (200 mol%) regio- and stereocontrolled synthesis of enantiopure
instead of H2O, adduct 2g with incorporation of two bridged bi- and tricyclic ketals via a selective cycloke-
deuterium atoms at the methylenic group was talization reaction of alkynyldioxolanes under pre-
achieved (Scheme 5). This double deuteration caused cious metal/Brønsted (or Lewis) acid-cocatalyzed con-
both the modification of the peaks at 3.10 and ditions. Further studies on the scope and synthetic ap-
3.87 ppm, which are the signals of the NCHH protons, plications of these reactions are currently in progress.
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-dioxabicycloACTHNUTRGNEUNG[4.2.1]nonane 2g. The
Experimental Section
fact that the gold-catalyzed conversion of alkynyldioxo-
lane 1g into tricycle 2g in the presence of 2 equiv. of
D2O afforded double deuterated product [D]-2g as
Typical Procedure for the Metal/Acid Co-Catalyzed
Cyclization to Bridged Acetals using
Alkynyldioxolane 1g
1
judged by H NMR spectroscopy and mass spectrom-
etry (see Supporting Information), suggests that deu-
terolysis of the carbon-gold bond in species 4 as well
as deuteration of species of type 9 have occurred
(Scheme 4).
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
sequentially added to a stirred solution of the alkynyldioxo-
lane (+)-1g (49 mg, 0.16 mmol) in dichloromethane
Scheme 5. Au(I)-catalyzed bis-oxycyclization reaction of alkynyldioxolane derivative 1g both in the presence of D2O and in
the absence of acid.
Adv. Synth. Catal. 2010, 352, 1277 – 1283
ꢄ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1281

Benito Alcaide et al.
COMMUNICATIONS
(0.16 mL). The resulting mixture was heated in a sealed
tube at 808C 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 (3ꢅ3 mL), and the
combined extracts were washed twice with brine. The organ-
ic extract was washed with brine, dried (MgSO4), concen-
trated under reduced pressure, and purified by flash column
chromatography on silica gel (hexanes/ethyl acetate=1:1) to
afford the product (+)-2g as a colorless solid; yield: 26 mg
(63%); mp 150–1528C; [a]D: +5.0 (c 1.1 in CHCl3);
1H NMR (300 MHz, CDCl3, 258C): d=7.44 (m, 5H), 4.66
and 4.57 (d, J=4.8 Hz, each 1H), 4.09 (m, 1H), 4.01 (dd,
J=8.1, 4.9 Hz, 1H), 3.87 (ddd, J=14.4, 5.4, 1.5 Hz, 1H),
3.79 (d, J=4.6 Hz, 1H), 3.63 (s, 3H), 3.10 (ddd, J=14.6,
12.0, 4.2 Hz, 1H), 2.34 (ddd, J=14.4, 12.2, 5.4 Hz, 1H), 1.94
(ddd, J=14.4, 3.9, 1.0 Hz, 1H); 13C NMR (75 MHz, CDCl3,
258C): d=168.2, 142.5, 128.2, 128.1, 124.7, 111.8, 83.5, 72.2,
71.2, 63.0, 59.2, 38.6, 36.5; IR (CHCl3): n=1748, 1190,
1044 cmÀ1; HR-MS (ES): m/z=276.1232, calcd (%) for
C15H18NO4 [M+H]+: 276.1236.
[4] Terminal alkynyldioxolanes 1a and 1d required for our
study were prepared from (R)-2,3-O-isopropylidenegly-
ceraldehyde or from 2-O-benzyl-d-threitol, respectively
(see Supporting Information for details). The terminal
alkynyldioxolanes 1f and 1i were prepared from imines
of (R)-2,3-O-isopropylideneglyceraldehyde as we previ-
ously described: a) B. Alcaide, P. Almendros, C. Ara-
goncillo, Chem. Commun. 1999, 1913; b) B. Alcaide, P.
Almendros, J. M. Alonso, M. F. Aly, C. Pardo, E. Sꢁez,
M. R. Torres, J. Org. Chem. 2002, 67, 7004. The methyl-
substituted alkynyldioxolanes 1c, 1h and 1k were pre-
pared through base-promoted O- or N-propargylation
(see Supporting Information for details). The phenyl-
substituted alkynyldioxolanes 1b, 1e, 1g and 1j were
prepared from 1a, 1d, 1f and 1i through Sonogashira
coupling (see Supporting Information for details).
[5] For a review on gold and protons, see: A. S. K.
Hashmi, Catal. Today 2007, 122, 211.
[6] Tricyclic acetals 2f–k possess as well a b-lactam moiety,
which in addition to being a versatile building block is
the key structural motif in biologically relevant com-
pounds such as antibiotics and enzyme inhibitors. For
selected reviews, see: a) R. Southgate, C. Branch, S.
Coulton, E. Hunt, In Recent Progress in the Chemical
Synthesis of Antibiotics and Related Microbial Products,
(Ed.: G. Lukacs), Springer, Berlin, 1993, Vol. 2, pp 621;
b) R. Southgate, C. Branch, S. Coulton, E. Hunt, Curr.
Org. Chem. 2002, 6, 245; c) G. Veinberg, M. Vorona, I.
Shestakova, I. Kanepe, E. Lukevics, Curr. Med. Chem.
2003, 10, 1741; d) B. Alcaide, P. Almendros, C. Aragon-
cillo, Chem. Rev. 2007, 107, 4437.
Acknowledgements
Support for this work by the DGI-MICINN (Projects
CTQ2006-10292 and CTQ2009-09318), CAM (Project
S2009/PPQ-1752), and UCM-BSCH (Grant GR58/08) are
gratefully acknowledged. R. C. thanks the MEC for a predoc-
toral grant.
[7] For gold-catalyzed hydration of alkynes, see: a) N.
Marion, R. S. Ramꢂn, S. P. Nolan, J. Am. Chem. Soc.
2009, 131, 448; b) A. Leyva, A. Corma, J. Org. Chem.
2009, 74, 2067; c) E. Mizushima, K. Sato, T. Hayashi,
M. Tanaka, Angew. Chem. 2002, 114, 4745; Angew.
Chem. Int. Ed. 2002, 41, 4563.
[8] X-ray data of 2g: crystallized from ethyl acetate/n-
hexane at 208C; C15H17NO4 (Mr =275.30); monoclinic;
space group=P21; a=11.3463(16) ꢆ, b=5.8344(8) ꢆ.;
References
[1] For selected reviews, see: a) B. Lipshutz, Y. Yamamoto
(Eds. ), Chem. Rev. 2008, 108, special issue 8; b) G. J.
Hutchings, M. Brust, H. Schmidbaur, ACTHUNRTGNEUNG(Eds. ), Chem.
Soc. Rev. 2008, 37, special issue 9; c) N. Bongers, N.
Krause, Angew. Chem. 2008, 120, 2208; Angew. Chem.
Int. Ed. 2008, 47, 2178; d) A. S. K. Hashmi, G. J. Hutch-
ings, Angew. Chem. 2006, 118, 8064; Angew. Chem. Int.
Ed. 2006, 45, 7896; e) J. Muzart, Tetrahedron 2008, 64,
5815; f) A. S. K. Hashmi, Chem. Rev. 2007, 107, 3180.
[2] For reviews on the construction of heterocycles by
alkyne p-activation, see: a) Y. Yamamoto, I. D. Grid-
nev, N. T. Patil, T. Jin, Chem. Commun. 2009, 5075;
b) S. F. Kirsch, Synthesis 2008, 3183; c) F. E. McDonald,
Chem. Eur. J. 1999, 5, 3103.
[3] See, for instance: a) B. Alcaide, P. Almendros, C. Ara-
goncillo, Chem. Eur. J. 2009, 15, 9987; b) B. Alcaide, P.
Almendros, T. Martꢀnez del Campo, M. T. Quirꢂs,
Chem. Eur. J. 2009, 15, 3344; c) B. Alcaide, P. Almen-
dros, R. Carrascosa, T. Martꢀnez del Campo, Chem.
Eur. J. 2009, 15, 2496; d) B. Alcaide, P. Almendros, R.
Carrascosa, M. C. Redondo, Chem. Eur. J. 2008, 14,
637; e) B. Alcaide, P. Almendros, T. Martꢀnez del
Campo, Angew. Chem. 2007, 119, 6804; Angew. Chem.
Int. Ed. 2007, 46, 6684; Angew. Chem. 2007, 119, 6804;
f) B. Alcaide, P. Almendros, T. Martꢀnez del Campo,
Angew. Chem. 2006, 118, 4613; Angew. Chem. Int. Ed.
2006, 45, 4501.
c=11.4061(16) ꢆ;
700.02(17) ꢆ3; Z=2; density (calc.)=1.306 mgmÀ3; m=
0.095 mmÀ1
(000)=292. transparent crystal of
0.45ꢅ0.19ꢅ0.10 mm3 was used. 2990 [R
(int)=0.0930]
b=112.014(2)
deg.;
V=
;
FN
A
AHCTUNGTRENNUNG
independent reflections were collected on a Bruker
Smart CCD difractomer using graphite-monochromat-
ed Mo-Ka radiation (l=0.71073 ꢆ) operating at 50 kV
and 30 mA. Data were collected over a hemisphere of
the reciprocal space by combination of three exposure
sets. Each exposure of 20 s covered 0.3 in w. The cell
parameters were determined and refined by a least-
squares fit of all reflections. The first 100 frames were
recollected at the end of the data collection to monitor
crystal decay, and no appreciable decay was observed.
The structure was solved by direct methods and Fourier
synthesis. It was refined by full-matrix least-squares
procedures on F2 (SHELXL-97). All non-hydrogen
atoms were refined anisotropically. All hydrogen atoms
were included in calculated positions and refined riding
on the respective carbon atoms. Final R(Rw) values
were R1=0.0863 and wR2=0.1696. CCDC 711398 con-
tains the supplementary crystallographic data for this
1282
asc.wiley-vch.de
ꢄ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 1277 – 1283

Gold/Acid-Cocatalyzed Regiodivergent Preparation of Bridged Ketals
paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif (or from The
Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge CB21EZ, UK; Fax (+44)-1223-
tion occurred on heating a solution of the above diol in
dichloromethane at 808C on a sealed tube in the pres-
ence of [AuClPPh3] (2.5 mol%)/AgOTf (2.5 mol%)/
FeCl3 (10 mol%). The fact that the reaction of aceto-
nide 1g catalyzed by the p-philic gold complex
336033; or deposit@cccdc.cam.ac.uk).
[AuACTHNUTRGNEU(GN OTf)PPh3] alone, in the absence of acid additive,
[9] Control experiments have ruled out the hypothesis of
Brønsted acid catalysis; although competition between
gold and Brønsted acids has been described, see: a) G.
Dyker, E. Muth, A. S. K. Hashmi, L. Ding, Adv. Synth.
Catal. 2003, 345, 1247; b) D. Kadzimirsz, D. Hilde-
brandt, K. Merz, G. Dyker, Chem. Commun. 2006, 661;
c) W.-J. Shi, Y. Liu, P. Butti, A. Togni, Adv. Synth.
Catal. 2007, 349, 1619, no conversion to acetal 2a was
observed from the reaction of alkynyldioxolane 1a in
the absence of gold salt.
proceeded to afford the corresponding ketal 2g, may
also support this order of steps: the ketal in species 3
attacks the alkyne and the resulting oxonium then is
hydrolyzed.
[12] For the the synthesis of acetals by gold-catalyzed attack
of diols onto alkynes, see: a) S. Antoniotti, E. Genin,
V. Michelet, J.-P. GenÞt, J. Am. Chem. Soc. 2005, 127,
9976; b) A. Diꢃguez-Vꢁzquez, C. C. Tzschucke, J. Cre-
cente-Campo, S. McGrath, S. V. Ley, Eur. J. Org.
Chem. 2009, 1698; c) L.-P. Liu, G. B. Hammond, Org.
Lett. 2009, 11, 5090.
[13] It has been demonstrated that an ether oxygen atom
can serve as an excellent nucleophile in reacting with
gold-coordinated alkynes, leading to an ether transfer:
H. J. Bae, B. Baskar, S. E. An, J. Y. Cheong, D. T.
Thangadurai, I.-C. Hwang, Y. H. Rhee, Angew. Chem.
2008, 120, 2295; Angew. Chem. Int. Ed. 2008, 47, 2263.
[14] X.-F. Wu, D. Bezier, C. Darcel, Adv. Synth. Catal. 2009,
351, 367.
[10] A. Duschek, S. F. Kirsch, Angew. Chem. 2008, 120,
5787; Angew. Chem. Int. Ed. 2008, 47, 5703.
[11] A mechanistic scenario involving the initial formation
of the 1,2-diol followed by bis-hydroalkoxylation is less
likely. A control experiment showed that the diol de-
rived from acetonide 1f did react in dichloromethane
at 808C 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 2f was not detected. No reac-
Adv. Synth. Catal. 2010, 352, 1277 – 1283
ꢄ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1283