PtCl4-catalyzed domino synthesis of fused bicyclic acetals

Article abstract of DOI:10.1002/anie.200704595

(Chemical Equation Presented) At sixes and sevens: The synthesis of [4.2.1]- and [3.2.1]-fused bicyclic acetals by an intramolecular double alkoxylation of alkyne diols is reported. The course of the reaction depends on the substitution of the triple bond

Full text of DOI:10.1002/anie.200704595

Angewandte
Chemie
DOI: 10.1002/anie.200704595
Domino Sequence
PtCl4-Catalyzed Domino Synthesis of Fused Bicyclic Acetals**
Alejandro DiØguez-Vµzquez, C. Christoph Tzschucke, Wing Yee Lam, and Steven V. Ley*
The search for new avenues to molecular complexity from
relatively simple substrates has been one of the major
objectives of organic chemists for the last decade.[1] In this
regard, domino reactions have been established as a powerful
tool to accomplish this goal, since it offers highly efficient
transformations by allowing the build up of complex struc-
tures in fewer steps and increased overall yields.[2] Following
this concept, transition-metal-catalyzed cycloisomerization
Scheme 1. Retrosynthetic analysis.
reactions of w-alkynols have been applied to the synthesis of
oxygen-containing heterocycles.[3,4] The intramolecular
nature of these transformations means that the regio- and
stereoselectivities are often excellent, thus permitting the
synthesis of a single compound after several bond-forming
reactions. We therefore reasoned that the development of
new approaches to the synthesis of structurally diverse
scaffolds would likely benefit from metal-catalyzed cyclo-
isomerization reactions.
Recently, our research group has employed butane 1,2-
diacetal (BDA) protected diols as a source of chiral informa-
tion in the synthesis of fused bicyclic acetals, some of which
have shown interesting cytotoxic properties.[5] Inspired by
these results, we decided to seek new approaches directed
towards the synthesis of heteroatom-containing fused bicyclic
acetals of general structure 1 (Scheme 1). We envisioned that
a Lewis acid catalyzed domino cycloisomerization-hydro-
alkoxylation reaction of a 6-heptyne-1,2-diol derivative 2
could be applied to the synthesis of bicyclic acetals 1.[6] By
taking advantage of the BDA-selective protection of the 1,2-
diol, the homochiral protected diol 3 could be prepared in a
few steps from the corresponding BDA-protected glyceral-
dehyde 4 or tartrate 5.[7] The high stereoselectivity in many of
the transformations performed using BDA derivatives, and
the fact that both enantiomers are available and easily
prepared on a multigram scale, make these substrates
attractive building blocks for the synthesis of small molecules.
Using alkyne diol 2a (Table 1, entry 1) as the starting
material, a series of experiments with different catalysts under
a number of reaction conditions was carried out. After this
optimization process we found that the use of 2mol% PtCl 4
in THFas the solvent afforded the desired bicyclic acetal 1a in
Table 1: Domino cycloisomerization-hydroalkoxylation reaction of
alkyne-diol derivatives 2 (R2, R3 =H; X=NTs).
Entry
Diol
R1
R4
Product
Yield[a]
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2 f
2g
2h
2i
H
CO2Me
H
H
Ph
1a[b]
93
80
77
82
75
81
89
83
1b
H
H
H
H
H
H
H
H
H
6c[b]
2-BrC6H4
3-ClC6H4
3-MeOC6H4
4-FC6H4
4-MeOC6H4
4-MeC6H4
4-CF3C6H4
4-NO2C6H4
6d[b]
6e
6 f
6g[b]
6h[b]
6i[b]
9
10
11
86
2j
2k
1j[b] +6j[b]
1k[b] +6k
75[c]
83[d]
[a] Yield of isolated product based on alkyne-diol 2. [b] Structure
unambiguously established by X-ray crystallography. [c] 1:2.5 mixture of
1j/6j. [d] 6:1 mixture of 1k/6k. Ts=toluene-4-sulfonyl.
[*] Dr. A. DiØguez-Vµzquez, Dr. C. C. Tzschucke, W. Y. Lam,
Prof. Dr. S. V. Ley
Department of Chemistry
University of Cambridge
Lensfield Road, Cambridge, CB2 1EW (UK)
Fax: ( +44)122-333-6442
E-mail: svl1000@cam.ac.uk
Homepage: http://leygroup.ch.cam.ac.uk
93% yield as a single diastereoisomer after 2h at room
temperature. Similarly, diol 2b was converted in 80% yield
into the enantiopure bicyclic g-amino ester 1b (Table 1,
entry 2).
[**] We thank Merck Research Laboratories for support through the
Academic Development Program (S.V.L.), the Ministerio de Edu-
cación y Ciencia (Spain) for a postdoctoral fellowship (A.D.V.), the
Deutsche Forschungsgemeinschaft for a postdoctoral fellowship
(C.C.T.), and the Ministry of Education (Singapore) for a student-
ship (W.Y.L.). We also thank Dr. John Davies at the Cambridge
University Chemistry Laboratory for X-ray crystallography.
By applying the same reaction conditions we further
explored the scope of this platinum-catalyzed double intra-
molecular hydroalkoxylation reaction with substrates 2c–k
that bear an aryl-substituted triple bond. In general, we
observed that internal triple bonds are less reactive in these
hydroalkoxylation reactions than terminal ones. Conse-
quently, a longer reaction time (16 h) was required until
thin-layer chromatography showed complete consumption of
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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209

Communications
the starting material and formation of a new product. To our
generating the diol 2 in situ,[13] which then should undergo a
double intramolecular hydroalkoxylation reaction of the
triple bond. Indeed, we found after some experimentation
that 2mol% PtCl 4 in acetic acid led to complete conversion of
the starting material into the bicyclic acetal. Although other
Lewis acids were able to cleave the BDA group and form the
diol 2 as well, only PtCl4 and AuCl3 could catalyze the
subsequent hydroalkoxylation reaction. Other solvent sys-
tems were not as effective for the domino sequence. In
particular, the addition of excess water (5% v/v) leads to
complete deactivation of the catalyst and no conversion of the
starting material was detected. Addition of trifluoroacetic
acid to the reaction mixture resulted in faster conversion;
however, we observed the formation of numerous decom-
position products. Acetic acid alone did not give any
conversion of the starting material, clearly demonstrating
that the platinum catalyst is necessary for both steps of the
domino reaction.
The cycloisomerization step of the domino reaction
proceeded with the same regioselectivity as already observed,
that is, terminal alkynes lead to [3.2.1]bicyclic acetals 1 by a 6-
exo pathway, whereas aryl-substituted alkynes give rise to
[4.2.1]bicycles 6 through a 7-endo cyclization (Table 2,
entries 1–8). The yields of the isolated products for the
domino process were generally good and comparable to the
cycloisomerizations of the corresponding alkyne diols. The
versatility of the BDA-protected building blocks allowed us
to easily access a number of propargylic ethers 3 (X = O) with
substituents at different positions (Table 2, entries 9–17).
These substrates also underwent the domino deprotection-
cyclization sequence in good yield.
surprise, the major isolated product in most cases was the
[4.2.1]bicyclic acetal 6, which arises from an initial 7-endo
cyclization, instead of the [3.2.1]bicyclic acetals 1, formed by
an initial 6-exo cyclization.[8] While the competition between
6-endo and 5-exo cycloisomerization reactions has been
extensively studied,[4e,9] to the best of our knowledge, only
one example of a 7-endo cyclization of an alkyne diol bearing
a dialkyl-substituted triple bond has been reported.[4d,10] The
structures of 6c, 6d, 6g–6j were confirmed by single-crystal
X-ray diffraction analysis.[11] The reaction proceeded in good
yield for substrates without a strong electron-withdrawing
substituent on the aromatic ring (2c–i), and gave the
homochiral bicyclic acetals 6c–i resulting from a 7-endo
cycloisomerization reaction with high selectivity (Table 1,
entries 3–9). However, the presence of an electron-withdraw-
ing substituent in the para position of the aromatic ring
diminishes the reactivity and changes the regioselectivity of
the cycloisomerization reaction. Thus, in the case of p-CF3
(2j) we observed a 1:2.5 ratio of the 6-exo product 1j to the 7-
endo product 6j (Table 1, entry 10), which could be separated
by column chromatography and their structures were con-
firmed by X-ray analysis. When the crude reaction mixture
was analyzed by NMR spectroscopy after three hours, the
enol ethers 7j and 8j were detected exclusively (Scheme 2).
The ratio between the 6-exo-dig enol ether 7j and the 7-endo-
dig enol ether 8j was the same as for the final products (1:2.5),
A plausible mechanism for the cycloisomerization-hydro-
alkoxylation reaction is depicted in Scheme 3. Coordination
of the platinum catalyst to the alkyne 2 provides the p-
complex 9 in which the triple bond is activated towards an
intramolecular nucleophilic attack by one of the hydroxy
groups.[14] This step proceeds in such a way that the metal
migrates to the sterically less encumbered position, and
nucleophilic attack occurs at the end of the triple bond where
the developing positive charge is best stabilized.[3b] Thus,
terminal alkynes cyclize by the 6-exo pathway, whereas the
cyclization of arylalkynes proceeds almost exclusively by the
7-endo pathway. Subsequent proton transfer leads to the enol
ether 7 or 8, respectively. In one case we were able to observe
the initial formation of both enol ethers, which strongly
supports their role as intermediates in the reaction.[15] Finally,
the corresponding fused bicyclic acetals 1 or 6 are formed by a
proton or Lewis acid catalyzed intramolecular hydroalkox-
ylation. In the cases where BDA-protected diols 3 are
employed, the described sequence is preceded by a Lewis
acid catalyzed deprotection of the substrate.
Scheme 2. The 6-exo-dig versus the 7-endo-dig cyclization reaction of
diol 2j.
which supports the hypothesis that these enol ethers are
indeed intermediates in the formation of the fused bicyclic
acetals. Both enol ethers could be isolated after column
chromatography.[12] The strongly electron-withdrawing nature
of the p-NO2 group in 2k resulted in the reaction proceeding
much more slowly and, notably, the major isolated product
was the fused bicyclic acetal 1k arising from a 6-exo
cyclization. However, the formation of several unidentified
side products was observed in this reaction.
In the present study we have described for the first time
the synthesis of [4.2.1]- and [3.2.1]-fused bicyclic acetals by an
intramolecular double alkoxylation of alkyne diols. The
course of the reaction depends on the substitution of the
triple bond. Terminal alkynes give the [3.2.1]bicyclic product
by a 6-exo pathway, whereas arylalkynes undergo a 7-endo
cyclization to the [4.2.1]bicycles.
Encouraged by these results we decided to explore
whether the platinum catalyst could directly convert the
BDA-protected substrate 3 into the desired bicyclic acetal
product by
a
domino deprotection-hydroalkoxylation
sequence. Since acetal protecting groups can generally be
removed by acid treatment, we reasoned that the Lewis acid
catalyst should be capable of cleaving the BDA group and
210
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Angew. Chem. Int. Ed. 2008, 47, 209 –212

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Table 2: Domino BDA cleavage-hydroalkoxylation reaction of the BDA derivatives 3.
substituted alkyne substrates, and
exploiting this new synthetic strat-
egy to obtain a number of structur-
ally diverse compounds for subse-
quent biological evaluation.
Received: October 4, 2007
Keywords: cyclization ·
.
domino reactions ·
fused-ring systems ·
hydroalkoxylation · platinum
Entry
BDA
R1
R2
R3
R4
X
Product
Yield[a]
1
2
3
4
5
6
7
8
3a
diast-3a
3c
3d
3e
3g
3i
3j
3l
3m
3n
ent-3o
diast-3p
3q
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
C11H23
Pr
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Bn
H
H
H
NTs
NTs
NTs
NTs
NTs
NTs
NTs
NTs
O
O
O
O
O
1a
ent-1a
6c
6d
6e
6g
6i
1j+6j
1l
1m
1n
92
88
75
77
65
78
72
63[b]
84
85
80
74
79
75
72
57
Ph
2-BrC6H4
3-ClC6H4
4-FC6H4
4-MeC6H4
4-CF3C6H4
H
H
H
H
H
H
H
Ph
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9
CH2OBn
CH2OTs
CH2OCH2-4-BrC6H4
(CH2)2CHCH2
H
H
H
10
11
12
13
14
15
16
ent-1o
ent-1p
1q
O
O
O
3r
3s
1r[c]
6s
CH2OCH2-4-BrC6H4
H
[a] Yield of isolated product based on BDA-derivative 3. [b] 1:2.5 mixture of 1j/6j. [c] Structure
established by X-ray crystallography. Bn=benzyl.
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Scheme 3. Proposed mechanism for the domino cycloisomerization-
hydroalkoxylation reaction.
The overall process allows for the straightforward syn-
thesis of structurally complex acetals from simple starting
materials. By using well-established BDA methodology,
substrates with a variety of substitution patterns are easily
accessible. Conveniently, not only the free diols but also the
BDA-protected ones could be employed, thereby obviating
the need for a separate deprotection step. Ongoing work in
our research group is directed towards further exploring the
substrate scope of the reaction, in particular with bisalkyl-
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Communications
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[15] This particular observation is in contrast to the mechanistic
proposal described in Ref. [4d].
212
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