Lewis acid catalyzed intramolecular [4+2] and [3+2] cross-cycloaddition of alkynylcyclopropane ketones with carbonyl compounds and imines

Article abstract of DOI:10.1002/anie.201200450

One brick, two bridges: The choice of the catalyzing Lewis acid (LA, π: π-electrophilic, π: π-electrophilic) determines the pathway ([4+2] or [3+2]) of catalytic intramolecular cycloaddition reactions (IMCCs) of alkynylcyclopropane (ACP) ketone. This method provides a general strategy for stereoselective construction of structurally diverse bridged oxa-/aza-[n.3.1] and oxa-/aza-[n.2.1] skeletons (see scheme). Copyright

Full text of DOI:10.1002/anie.201200450

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DOI: 10.1002/anie.201200450
Cycloadditions
Lewis Acid Catalyzed Intramolecular [4+2] and [3+2] Cross-
Cycloaddition of Alkynylcyclopropane Ketones with Carbonyl
Compounds and Imines**
Yu Bai, Weijie Tao, Jun Ren, and Zhongwen Wang*
The structurally diverse and complex family of compounds
that have bridged oxa/aza-[n.2.1] and oxa/aza-[n.3.1] skele-
tons (n = 2, 3, 4) widely occurs in nature and exhibits a broad
range of biological activities (Scheme 1). Additionally, such
bridged skeletons can also be used as key intermediates in
organic synthesis because of their inherent stereochemistry
and multiple functionalizable sites.[1] A general strategy for
the construction of medium-sized carbocycles may be pro-
Scheme 2. Oxa-/aza-[n.2.1] or oxa-/aza-[n.3.1] skeletons used as key
intermediates in organic synthesis. FG=functional group.
À
À
vided by C O or C N bond cleavage in bridged skeletons
(Scheme 2).[2–5] As important substructures that are prevalent
in natural products, cis-2,5-disubstituted tetrahydrofuran/
pyrrolidine and cis-2,6-disubstituted tetrahydropyran/piperi-
À
dine may also be obtained by C C bond cleavage (Scheme 2).
The development of a general strategy to construct such
differently bridged skeletons is important for both the
synthesis of natural products and the construction of structur-
ally diverse molecular libraries for chemical biology and the
discovery of pharmaceutical and agrochemical leads.
Cycloaddition and domino reactions belong to the most
efficient and direct transformations of cyclic skeletons.
Although various cycloaddition and domino reactions have
been developed for construction of such bridged skeletons,[6,7]
most of them focus on the synthesis of one type or one
subclass of the big and structurally diverse family of [n.2.1]
and [n.3.1] skeletons, and development of a more general,
efficient, and conceptually new strategy still remains impor-
tant and challenging.
Alkynylcyclopropane (ACP) ketone has recently been
introduced as a useful all-carbon 1,4-dipole. Zhang and
Schmalz reported a Lewis acid (LA) catalyzed domino
cycloisomerization/nucleophilic ring-opening process of
ACP ketones.[8] Subsequently Zhang and co-workers devel-
oped a gold-catalyzed intermolecular [4+2] cycloaddition of
ACP ketones with alkenes, carbonyl compounds, and imi-
nes.[9a] Some other types of cycloadditions have also been
successfully developed by Zhang and co-workers, and by our
research group.[10] We have recently developed a general
strategy for construction of bridged oxa- and aza-[n.2.1]
skeletons and have successfully applied it to the total
synthesis of platensimycin and bruguierol.[11,12] We also
described a novel intramolecular cross-cycloaddition reaction
(IMCC) on two types of functionalized cyclopropanes, which
were used as all-carbon 1,3-dipoles. We hoped to apply this
IMCC on ACP ketone to develop a [4+2] IMCC as a general
strategy for construction of oxa- and aza-[n.3.1] skeletons
(Scheme 3). Moreover, the difference between p-electro-
philic (p-LAs) and s-electrophilic (s-LAs) LAs was consid-
Scheme 1. Representative natural products containing oxa-/aza-[n.2.1]
or oxa-/aza-[n.3.1] skeletons.
[*] Dr. Y. Bai,[+] W. Tao,[+] J. Ren, Prof. Z. Wang
State Key Laboratory of Elemento-Organic Chemistry
Institute of Elemento-Organic Chemistry, Nankai University
Tianjin 300071 (P. R. China)
E-mail: wzwrj@nankai.edu.cn
Homepage: http://wzw.nankai.edu.cn
[+] These two authors contributed equally to this work.
[**] We thank the National Natural Science Foundation of China,
National Key Project of Scientific and Technical Supporting
Programs (973 Program) (2010CB126106), National Key Technol-
ogies R&D Program (2011BAE06B05), and the “111” Project of the
Ministry of Education of China (B06005) for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201200450.
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Scheme 3. Concept of LA-regulated [3+2] and [4+2] IMCC.
ered[13], as demonstrated in the studies by Zhang and co-
workers[10b] and by our research group[10c] on reactions of ACP
ketones with nitrones. We therefore envisioned that by an
appropriate selection of the LA, the cycloaddition mode of an
ACP ketone with a carbonyl compound or imine might be
switched between [3+2] IMCC (path A) and [4+2] IMCC
(path B), and thus a more general strategy for construction of
both [n.2.1] and [n.3.1] skeletons could be developed.
Compound 1a was prepared as a model substrate to verify
the concept, and various LAs were tested with 1,2-dichloro-
ethane as solvent (Table 1). Most of the investigated LAs
catalyzed the IMCC and gave [4+2] and/or [3+2] cyclo-
adducts in various ratios. In most cases, the [4+2] or
Scheme 4. Construction of oxa-[3.2.1] and oxa-[3.3.1] skeletons. Reac-
tion conditions (0.3 mmol scale): PPh3·AuCl/AgOTf (10 mol%),
(CH2Cl)2 (10.0 mL), 60–708C, 0.5–2 h, under Ar. All yields reported are
those of isolated products. [a] AgNTf2 was used instead of AgOTf.
structure of 3d was unambiguously confirmed by NMR
spectroscopy, HRMS analysis, and X-ray crystal structure
analysis[14] (Figure 1).
[3+2] cycloadduct was obtained as a major product
Table 1: [3+2] and/or [4+2] IMCC catalyzed by various Lewis acids.[a]
by catalysis with p-LAs or s-LAs, respectively. Some
LAs showed excellent reaction selectivity between
the [4+2] and [3+2] IMCC, for example, PPh3·AuCl/
AgOTf gave [4+2] cycloadduct 2a (Table 1, entry 1)
and Ni(ClO4)2·6H2O gave [3+2] cycloadduct 3a
(Table 1, entry 14), both as sole products in good
yields. These conditions were used for the subse-
quent investigation. By selecting suitable LAs,
bridged oxa-[3.2.1] or oxa-[3.3.1] skeletons could
be constructed selectively. It should be noted that
triflic acid (Brønsted acid) also gave [3+2] and [4+2]
cycloadducts (Table 1, entry 20). To the best of our
knowledge, this is the first intramolecular cyclo-
addition and also the first [3+2] cycloaddition of
ACP ketone.
For construction of oxa-[n.3.1] skeletons, various
ACP ketones 1 were prepared and subsequently
subjected to [4+2] IMCC with carbonyl compounds
(Scheme 4). Substrates with various substituents
afforded oxa-[3.2.1] and oxa-[3.3.1] skeletons. The
structure of 2d was confirmed by NMR spectrosco-
py, HRMS analysis, and X-ray crystal structure
analysis[14] (Figure 1). Formation of the oxa-[4.3.1]
skeleton failed, however we were delighted that
construction of the aza-[4.3.1] skeleton was success-
ful (see below).
Entry
Lewis acid
T [8C]
t
2a
[%]
3a
[%]
1a
Yield
[%][c]
[%][b]
1
2
3
4
5
6
7
8
PPh3·AuCl/AgOTf
Cu(OTf)2
AuCl3
60–70
60–70
60–70
60–70
60–70
60–70
60–70
60-70
60–70
60–70
60–70
60–70
60–70
60–70
60–70
RT
2 h
2 h
3 h
3 h
2 h
4 h
1 h
4 h
4 h
1 h
3 h
4 h
3 h
4 h
4 h
93
85
82
60
59
54
45
31
10
9
6
4
3
0
0
0
0
0
0
3
3
0
41
0
0
0
0
15
27
42
28
70
48
59
19
21
11
37
0
1
5
0
0
8
0
15
30
0
0
54
0
6
52
0
0
0
0
0
93
88
85 (90)
60
100
54 (62)
45
31 (46)
10 (40)
24
33
46 (100)
31
70 (76)
48 (100)
59
19
21
11
52
CuOTf
Bi(OTf)3
Zn(OTf)2
Hg(OTf)2
PtCl2
9
Pd(OAc)2
FeCl3·6H2O
In(OTf)3
Yb(OTf)3
Sn(OTf)2
Ni(ClO4)2·6H2O
Sc(OTf)3
BF3·OEt2
TMSOTf
TiCl4
10
11
12
13
14
15
16
17
18
19
20
17 min
22 min
25 min
30 min
35 min
60–70
RT
RT
SnCl4
triflic acid
0
15
Ni(ClO4)2·6H2O was selected as LA catalyst for
[3+2] IMCC (Scheme 5). Oxa-[2.2.1] and oxa-[3.2.1]
skeletons were constructed successfully, and prod-
ucts with a high diversity of substituents were
obtained in most cases with moderate to excellent
yields, and with excellent stereoselectivities. The
55
[a] Reaction conditions: 1a (10 mg, 0.039 mmol) in (CH2Cl)2 (3 mL), Lewis acid
(10 mol%), yields determined by 1H NMR spectroscopy (internal standard: 1-
chloro-2,4-dinitrobenzene). [b] Recovered starting material. [c] Yields based on
recovered starting material are given in parentheses. Tf=trifluoromethanesulfonyl,
TMS=trimethylsilyl.
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Figure 1. X-ray crystal structures of 2d and 3d. Thermal ellipsoids are
set at 50% probability.
Scheme 6. Construction of aza-[n.3.1] skeletons. Reaction conditions
(0.4 mmol scale): Yb(OAc)3 (1.05 equiv), 4 ꢀ M.S., CH3CN (30 mL),
2 h, RT; after filtration and evaporation: PPh3·AuCl/AgOTf (10 mol%),
(CH2Cl)2 (20 mL), 60–708C, 0.5–2 h, under Ar. All yields reported are
those of isolated products. M.S.=molecular sieves.
Scheme 7. Domino and stepwise [4+2] IMCC and [4+2] Diels–Alder
reaction.
Scheme 5. Construction of oxa-[2.2.1] and oxa-[3.2.1] skeletons. Reac-
tion conditions (0.3 mmol scale): Ni(ClO4)2·6H2O (10 mol%),
(CH2Cl)2 (10.0 mL), 60–708C, 0.5–2 h, under Ar. All yields reported are
those of isolated products. [a] Sc(OTf)3 was used instead of Ni-
(ClO4)2·6H2O.
Scheme 8. An intermolecular [3+2] cycloaddition.
An attempt to achieve a [3+2] IMCC of ACP ketones
with imines failed under catalysis with Ni(ClO4)2·6H2O,
because of the quick decomposition of the substrates. How-
ever, after formation of the imine,[15] the [4+2] IMCC was
successful under catalysis with PPh3·AuCl/AgOTf, and aza-
[3.2.1], aza-[3.3.1], and even aza-[4.3.1] skeletons were
successfully constructed (Scheme 6).
diesters in which a 2,5-cis-disubstituted tetrahydrofuran was
obtained.[17]
In summary, we have successfully developed a general
strategy for construction of structurally diverse bridged oxa-/
aza-[n.3.1] and oxa-/aza-[n.2.1] skeletons by a novel [4+2] and
[3+2] IMCC of ACP ketones with carbonyl compounds and
imines. This method also supplied a potential general strategy
for construction of medium-sized carbocyclic skeletons.
Features of this strategy include good structural diversity,
LA-regulated selective formation of [n.3.1] and [n.2.1]
skeletons from common starting materials, excellent stereo-
selectivity, and mild conditions. To the best of our knowledge,
this is the first intramolecular cycloaddition and the first
intermolecular [3+2] cycloaddition of ACP ketones. These
results indicated the potential use of ACP ketones as multi-
functional building blocks in organic synthesis. Future studies
will include investigation of the [4+2] or [3+2] IMCC strategy
and development of the intermolecular [3+2] cycloaddition,
including potential applications on natural products synthesis.
Polycyclic skeletons with fused six-membered carbocycles
are prevalent in natural and synthetic products (e.g., Kaganꢀs
ether[16]). A Diels–Alder cycloaddition of 2d with dimethyl
acetylenedicarboxylate (DMAD) was carried out under
heating in toluene and gave a 6-8-6 carbocyclic core skeleton
.
(5a:5b = 1:1.2; Scheme 7). Under catalysis by PPh3 AuCl/
AgNTf2, an efficient one-pot domino variant of this reaction
has also been developed successfully.
An intermolecular [3+2] cycloaddition of ACP ketone 6
with 4-methylbenzaldehyde was also carried out (Scheme 8).
This is the first intermolecular [3+2] cycloaddition of an ACP
ketone. The method afforded 2,5-trans-disubstituted tetrahy-
drofuran 7 as a sole isomer, the high diastereoselectivity of
which was quite different from that of cyclopropane 1,1-
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Published online: March 12, 2012
Keywords: cycloadditions · cyclopropane · Lewis acids ·
.
medium-ring compounds · natural products
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