Gold-catalyzed dealkoxylative carbocyclization/[3+3] annulation cascade of acetal-allene or ketal-allene substrates

Article abstract of DOI:10.1002/chem.201000041

(Chemical Equatation Reprentation) Rapid construction: We report the first successful implementation of a catalytic tandem carbocyclization/annulation cascade reaction (e.g., see scheme) using acetal-allene or ketal-aliene substrates through a dealkoxylat

Full text of DOI:10.1002/chem.201000041

DOI: 10.1002/chem.201000041
Gold-Catalyzed Dealkoxylative Carbocyclization/ACTHNUGRTNEUNG[3+3] Annulation Cascade
of Acetal–Allene or Ketal–Allene Substrates
Tse-Min Teng, Ming-Shiun Lin, Dhananjayan Vasu, Sabyasachi Bhunia,
Ting-An Liu, and Rai-Shung Liu*[a]
Transition-metal catalyzed cyclization/annulation cascade
is a powerful tool to access complex polycyclic skeletons.[1]
Such reactions have been studied on oxo–alkyne substrates
(I)[1–3] with a representative example depicted in Scheme 1.[4]
In contrast, the tandem cyclization/annulation cascade re-
mained less studied for oxo–alkene and oxo–allene sub-
strates (II–III). We reported[5] gold-catalyzed deoxygenative
too unstable to isolate. Treatment of acetal 1a with allylsi-
lane (2.2 equiv) and PPh3AuSbF6 (5 mol%) in CH2Cl2
(258C, 3 min) delivered double-addition product 2 (trans/cis
10:1)[10,11] in 78% yield (Scheme 2). We also examined this
dealkoxylative carbocyclization in CH2Cl2 (258C) over com-
monly acidic catalysts (5 mol%), which provided the desired
compound 2 with the following optimized time and yields:
Nazarov[6]
cyclization/annula-
tion reactions of cis-2,4-dien-1-
als that serve as the first cycli-
zation/annulation cascade reac-
tion for oxo–alkene substrates
II. The success of this process
relies on sequential generation
of an allylic cation such as spe-
cies V, to enable a [4+3] annu-
lation with allylsilane. Herein,
we report the first success of
this catalytic cascade on acetal–
allene or ketal–allene substrates
through an initial Prins[7] cycli-
zation. The use of this new cat-
alysis is its potential access to
the central cores of bioactive or
natural products DK-002,[8] di-
chroanal B
and
taiwania-
quinol A–D.[9]
Scheme 1. Metal-catalyzed tandem cyclization/annulation cascade of oxo–alkyne and oxo–alkene substrates.
We prepared substrate 1a
bearing an acetal functionality
because its aldehyde form was
AuCl3 (1 h, 70%), AuCl (1 h, 22%), AgSbF6 (2 h, 14%),
AgOTf (4 h, 34%), Cu
ACHTUGNRTEN(NUGN OTf)2 (4 h, 54%), FeCl3 (1 h, 43%),
In(OTf)3 (30 min, 19%), PtCl2/CO (3 h, 3%), BF3·OEt2
AHCTUNGTRENNUNG
(08C, 30 min, 35%), TMSOTf (08C, 20 min, 17%), p-TSA
(5 h, 17%) and HOTf (3 h, 5%); all these catalysts led to
complete consumption of starting material 1a. As expected
the reaction failed with the use of p-TSA and HOTf because
of protonation of allylsilane.[10]
[a] T.-M. Teng, M.-S. Lin, D. Vasu, S. Bhunia, Dr. T.-A. Liu,
Prof. Dr. R.-S. Liu
Department of Chemistry, National Tsing-Hua University
Hsinchu, 30043, Taiwan (ROC)
Fax : (+886)3-5711082
E-mail: rsliu@mx.nthu.edu.tw
The dication equivalent of acetal 1a enables one-pot con-
struction of complicated carbocyclic or heterocyclic species
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000041.
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Chem. Eur. J. 2010, 16, 4744 – 4748

COMMUNICATION
yield, entries 8–11). A good ratio 12a/12b 7.1:1 was ob-
tained for compound 12 after treatment of the crude prod-
ucts with p-TSA (10 mol%) in hot THF (608C, 3 h). Simul-
taneous generation of three new cyclic rings with stereocon-
trol reflects the versatility of this approach to access molecu-
lar complexity of products.
Scheme 2. Gold-catalyzed double-addition reaction of 1a with allyltrime-
thylsilane.
Table 1. Carbocyclization/ACHTUNTRGNEUNG[3+3]-annulation cascade of acetal–allenes and ketal–allenes with allylsilanes.
4–13, through a dealkoxylative
carbocyclization/[3+3]-annula-
ACHTUNGTRENNUNG
tion cascade with suitable 2-
substituted allylsilanes 3a–3 f.
Notably, these products bear
1,1-dimethylfluorene skeletons
that are the central core struc-
ture of naturally occurring com-
pounds such as dichroanal B
and taiwaniaquinol A–D (see
Scheme 1).[9] A summary of the
results is provided in Table 1.
Treatment of 1a with 2-phenyl-
allylsilane (3a; 1 equiv) and
Entry
Substrate[a]
Silane (equiv)
t [min]
Product (Yield [%])[b]
1
2
3
1a
1a
1a
5
3a (2.0)
20
10
4a (3), 1:1
4b (82), d.r. >20:1
PPh3AuSbF6
(5 mol%)
in
CH2Cl2 (258C) gave tricyclic
compounds 4a (isomeric ratio
1:1) and 4b in 76 and 9% yield,
respectively (entry 1). Herein,
an increased amount of silane
3a (2 equiv) led to a significant
formation of 4b in 82% yield
(entry 2), of which the structure
was determined with 1H NOE
spectroscopy. The use of 2-si-
loxymethyl- or 2-silylmethylal-
lylsilane (3b or 3c) produced
carbocyclic species 5 (d.r. 8.0:1)
and 6 (a/b 4.2:1) in 63 and 78%
yield, respectively (entries 3–4).
This new gold catalysis is appli-
cable even to the stereoselec-
tive synthesis of tetracyclic
furan and pyran species 7 and
8, which were obtained in 50
and 36% yield, respectively
4
1a
10
(78) 6a/6b 4.2:1
5
6
7
8
1a
1a
1a
1b
240
240
15
3b (1.0)
30
(entries 5–6).
Gold-catalyzed
9
1c
1b
3b (1.0)
3c (1.0)
30
10
11: R = nPr (64), d.r. 11.1:1[c]
annulation of acetal 1a with
silane 3 f led to formation of
complex carbocyclic compound
9 in 61% yield with d.r. 3.1:1
(entry 7). This gold catalysis
can be extended to the annula-
tion of ketal species 1b and 1c
with silanes 3b, 3c and 3 f to
give aldehydes 10–11, tricyclic
product 12 and spiro compound
13 in good yields (> 61%
10
11
1b
3 f (1.0)
20
[a] [substrate]=0.02m. [b] Product yields are given after purification from a silica column. [c] d.r. values are
obtained after treatment of the crude product with triethylamine in CH2Cl2 at 258C for 16 h. [d] This structure
represents stereochemistry of the major diastereomer. [e] p-TSA treatment in hot THF (608C, 3 h).
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R.-S. Liu et al.
Table 2. Carbocyclization/annulation cascade of acetal–allenes and
ketals–allenes with phenol and 1,3-diketones.
We also prepared acetals 1d–f by varying their allenyl
substituents. As depicted in Scheme 3, gold-catalyzed [3+3]
annulations of these substrates with silane 3b proceeded
smoothly to give corresponding tricyclic aldehydes 14a–b,
15b and 10 in moderate to good yields; their structures
Entry Substrate[a]
Nucleophile
t
Product (Yield [%])[b]
[min]
1
were determined by H NOE spectroscopy. For trisubstitut-
ed allene 1 f, its annulation product 10 was also obtained al-
ternatively from ketal 1b following the same gold catalytic
reaction (Table 1, entry 8).
1
10
15
2
3
16a
16a
15
40
18 (90)
Scheme 3. Gold-catalyzed cyclization of various acetals with silane 3b.
4
5
1a
1a
The additional utility of this catalysis is highlighted by the
availability of new complicated oxacyclic skeletons using
phenol derivative 16a or enolizable ketones 16b–c; the re-
sults are shown in Table 2. Unlike preceding carbocyclic
compounds, these oxacyclic compounds worked well with
various Lewis and Brønsted acids.[12] [3+3] Annulation of
acetal 1a with phenol 16a afforded desired compound 17 in
91% yield (entry 1). Notably, the annulation reaction of
acetal 1 f and ketal 1b with phenol 16a gave one identical
product 18 (entries 2–3). For 1a, the annulation with cyclic
1,3-diketones 16b–c gave oxacyclic ketones 19 and 20 in 46
and 61% yield, respectively (entries 4–5). This catalysis is
applicable to nonaromatic substrate 1g that gave distinct ox-
acyclic skeletons 21 and 22, via its [3+2] annulations with
phenol 16a and 1,3-diketone 16c, respectively (entries 6–7);
the molecular structure of compound 21 was confirmed by
X-ray diffraction study.[13]
40
30
6
7
16a
16c
1g
30
Equation (1) shows a 13C-labeling experiment to clarify
the reaction mechanism. We prepared [13C]-1a with a 10%
13C content at its allenyl =CH carbon. Gold-catalyzed annu-
lation of this species with 2-phenylallylsilane gave resulting
[13C]-4b with the 13C enrichment only occurring at the in-
denyl C(3)–H carbon. This information unambiguously ex-
cludes two possible pathways, including a) a direct allylation
of acetal in the initial step, and b) gold p-allene activated a
transfer of methoxy to the allenyl CH carbon.[14,15]
[a] [Substrate]=0.02m. [b] Product yields are given after purification
from a silica gel column.
Scheme 4 depicts a plausible mechanism involving an ini-
tial Prins cyclization of acetal 1a by PPh3AuSbF6 to give
oxonium species A. A subsequent carbocyclization of this
species generates allylic cation B, which reacts with 2-phe-
nylallylsilane 3a to give allylation product C with its me-
thoxy group stabilizing trimethysilyl group. We envisage the
oxonium functionality of species C triggers intramolecular
cyclization to generate tertiary cation D, inducing a second
allylation to deliver observed product 4b. This mechanism
also rationalizes the formation of tetracycylic species F, via
sequential formation of two carbocyclic rings of initial inter-
mediate C’, ultimately giving tertiary cation E and species F.
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Gold Catalysis
COMMUNICATION
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Scheme 4. A plausible formation mechanism of compound 4b and spiro
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In summary, we report the first success to implement a
catalytic tandem carbocyclization/annulation cascade on
acetal–allene or ketal–allene substrates.[17] Annulation of
these substrates with 2-substituted allylsilanes, phenol and
enolizable ketones enables a rapid construction of carbocy-
clic and oxacyclic frameworks with good stereocontrol for
most cases. The value of this annulation is also highlighted
by its potential access to the central core structures of bioac-
tive or natural products DK-002,[8] dichroanal B and taiwa-
niaquinol A–D.[9] The use of this method for synthesis of
natural compounds is under future investigation.
Experimental Section
A
solution of ClAuPPh3 (7.4 mg, 0.015 mmol) and AgSbF6 (5.1 mg,
0.015 mmol) in CH2Cl2 (13 mL) was stirred at 258C for 10 min before ad-
dition of acetal 1a (66 mg, 0.30 mmol) and silane 3b (65 mg, 0.30 mmol)
in CH2Cl2 (2 mL) with syringe pump during 30 min. The mixture was
kept stirring for 10 min before the solution was filtered over a short silica
bed. The solvent was evaporated under reduced pressure and the crude
product was eluted through a silica gel column. The two diastereomeric
products were then treated with Et3N in CH2Cl2 at room temperature for
16 h to afford aldehyde product 5 (43 mg, 0.19 mmol, 63%, d.r. 8.0:1).
[10] Treatment of PPh3AuSbF6 with allylSiMe3 under running conditions
did not generate PPh3AuACTHNUTRGNEUG(N allyl) species, see: Y.-C. Hsu, S. Datta, C.-
M. Ting, R.-S. Liu, Org. Lett. 2008, 10, 521.
[11] The major diastereomer of compound 2 was assigned to be the trans
isomer because it was separated into two components on a chiral
column (OD-H, hexane).
[12] Production of oxacyclic compounds 17 and 20 are efficient for
common acid catalysts; see Supporting Information (Tables S1 and
S2 in the Supporting Information).
[13] CCDC-727899 (21) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif.
Acknowledgements
The authors thank National Science Council, Taiwan for support this
work.
[14] Gold–p-allene complex may induce an intramolecular methoxy
attack to give gold–alkenyl oxonium species G according to gold p-
alkyne chemistry.[15] This process also generate hypothetic intermedi-
ate B through ionization of intermediate H. Nevertheless, this path-
Keywords: allenes · annulation · carbocyclization · cascade
reactions · gold
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R.-S. Liu et al.
way is expected to give desired product [13C]-4b with 13C occurring
at its indenyl C(1) and C(3) carbons. .
hyde 5. For acetal–allene 1 f, the initial allyl cation B’ is proposed to
be inactive toward allylation to avoid formation of a tertiary carbon.
This species likely undergoes a 1,4-methoxy transfer to give cation
B’’ that is more active for the allylation. .
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Fürstner, H. Szillat, F. Stelzer, J. Am. Chem. Soc. 2000, 122, 6785.
[16] For the formation of aldehyde 5 from substrate 1a, we propose that
the first allylation product C’ is subject to ionization that is triggered
by a cyclization/Pinacol rearrangement cascade to give desired alde-
[17] Carbocyclization of oxo–allene substrates has one precedent; see J.
Montgomery, M. Song, Org. Lett. 2002, 4, 4009.
Received: January 8, 2010
Published online: March 22, 2010
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