4-exo cyclizations by template catalysis

Article abstract of DOI:10.1002/anie.200904428

Small rings through large templates: A two-point binding of the substrate radicals to cationic titanocene templates is essential for the success of otherwise impossible 4-exo cyclizations (see scheme; Bn=benzyl). The cyclobutanes are obtained in high ster

Full text of DOI:10.1002/anie.200904428

Communications
DOI: 10.1002/anie.200904428
Template Catalysis
4-exo Cyclizations by Template Catalysis**
Andreas Gansꢀuer,* Dennis Worgull, Karsten Knebel, Inga Huth, and Gregor Schnakenburg
The cyclobutane ring is an important structural motif in many
natural products. A number of synthetic approaches to four-
membered rings have been described, but none of them is
general.[1] This is also the case for radical cyclizations, even
though they are in principle amongst the most powerful
reactions for the construction of carbocyclic rings. Difficulties
encountered in the preparation of cyclobutanes are caused by
Scheme 1. Cationic titanocene complexes and templated radical bind-
ing. Bn=benzyl.
their inherent strain and by the low rate constant of the
cyclization of the archetypal pentenyl radical.[2]
Therefore, the few efficient examples of 4-exo cyclizations
in classical free radical chemistry, and in metal-mediated and
[3]
metal-catalyzed radical reactions using SmI2
and
reaction of a tertiary radical renders the process thermody-
namically unfavorable. Our results of the first 4-exo cycliza-
tion without gem disubstitution are summarized in Scheme 2
and Table 1 (Coll = collidine = 2,4,6-trimethylpyridine).
titanocene(III) reagents[4] have to rely on special structural
features. In these cases, the presence of gem-dialkyl or gem-
dialkoxyl substitution[5] adjacent to the radical center[6] or the
incorporation of the cyclization into transannular tandem
sequences[7] was necessary for obtaining useful yields of the
desired products. A general access to cyclobutanes by the
4-exo cyclization is still elusive.
Herein, we address this issue by using cationic function-
alized titanocenes[8] as template catalysts for such reactions.
In these complexes the pendant amide ligand as well as the
chloride ligand can be replaced by polar groups. For a suitably
substituted radical this results in an energetically favorable
two-point binding to the template in which the radical center
and radical acceptor are forced into close spatial proximity.
As a consequence, the 4-exo cyclization becomes a trans-
annular transformation, which is thermodynamically and
kinetically more favorable. With careful adjustment of the
steric interactions this template effect can lead to highly
ordered intermediates and transition states, and hence to a
stereoselective cyclization (Scheme 1).
Scheme 2. Influence of template substitution on the 4-exo cyclization.
Table 1: Optimization of the 4-exo cyclization with 5.
Entry
5 [mol%]
t [h]
2/yield [%]
d.r.[a]
1
2
3
20
10
40
20
20
40
60
40
72
24
64
55
62
41
64
>95:5
>95:5
>95:5
>95:5
>95:5
We have realized the two-point binding with unsaturated
epoxides as radical precursors. Reductive electron transfer to
the epoxide generates a radical which is covalently attached
4[b]
5[c]
À
to titanium through a Ti O bond. The pivotal second binding
[a] Determined by 1H NMR spectroscopy. [b] Reaction temperature of
08C. [c] Reaction temperature of 688C.
can be enforced by a donor group displacing the amide ligand.
To this end, we chose 1 as the substrate, because a,b-
unsaturated carbonyl groups usually constitute better ligands
than the corresponding saturated carbonyl groups. The
From these investigations three points became clear, and
they lend conclusive support to our postulated template
mechanism. First, neither [Cp2TiCl2] (Cp = cyclopentadienyl)
nor any of the usually employed alkyl-substituted titanocenes
gave any 2, even though for substrates possessing gem-dialkyl
substitution these complexes can give excellent yields of
cyclobutanes.[6k] Instead, extensive decomposition of 1 was
observed. Therefore, the opening of a second coordination
site on titanium for templated radical binding is essential for
the synthesis of 2. The influence of the structure of the
template on the reaction is small but noticeable. The n-alkyl
chain in 3 proved to be superior to other groups. A bulkier
substituent such as the cyclohexylidene in the nonhygro-
[*] Prof. Dr. A. Gansꢀuer, Dr. D. Worgull, K. Knebel, I. Huth,
Dr. G. Schnakenburg
Kekulꢁ-Institut fꢂr Organische Chemie und Biochemie
and
Institut fꢂr Anorganische Chemie
Gerhard-Domagk-Strasse 1, 53121 Bonn (Germany)
Fax: (+49)228-73760
E-mail: andreas.gansaeuer@uni-bonn.de
[**] We thank the SFB 624 (Template-Vom Design chemischer Scha-
blonen zur Reaktionssteuerung) for continuing support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200904428.
8882
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Angew. Chem. Int. Ed. 2009, 48, 8882 –8885

Angewandte
Chemie
Table 2: Influence of epoxide substitution on the 4-exo cyclization.
scopic, air-stable complex 5, was sufficient to compensate for
this effect.
Second, the protic conditions[9] usually employed for
mediating turn-over are not suitable for the preparation of 2.
These unsuitable conditions must be the result of the cationic
complexes, as the presence of amides and hydroxy groups is
generally not detrimental to [Cp2TiCl2] or alkyl-substituted
titanocenes as catalysts.[9] The combination of Me3SiCl and
collidine as introduced by Oltra and Cuerva[10] is suitable to
this end. In titanocene-catalyzed epoxide openings, this
reagent combination is superior to Me3SiCl,[11] which was
introduced by Fꢀrstner et al. in his seminal catalytic reac-
tions.[12] It appears that only the silylated product can be
displaced by the substrate from the template, because 2 is an
excellent ligand for the titanocenes.
Entry
Substrate/R
t [h]
Product [%]
d.r.[a]
1
2
3
4
5
6/Et
8/nPr
10/nBu
12/nOct
14/Cy
40
60
40
72
40
7/63
9/70
11/63
13/60
15/46
90:10
87:13
90:10
88:12
68:32
[a] Determined by 1H NMR spectroscopy. Cy=cyclohexyl.
Third, the cyclization is completely diastereoselective at
temperatures ranging from 0 to 708C (refluxing THF). This is
remarkable in two respects. First, 4-exo cyclizations of
substrates similar to 1, without templated radical binding,
have been predicted to proceed without diastereoselectivi-
ty.[6k] For substrates identical to 1 but containing a gem-
dimethyl substitution, the cyclizations proceed with low
selectivity. Second, in contrast to typical radical cyclizations
the diastereoselectivity of our reaction is not temperature
dependent.
Scheme 4. Dependence of the templated 4-exo cyclization on amide
substitution.
The selectivity of our reactions can be explained by a two-
point binding of the radical intermediate (Scheme 3). The
templated cyclic radical will be more stable as conformer A,
leading to the trans product. Therefore, the transannular
cyclization should be diastereoselective over a wide temper-
ature range as indeed observed.
crystallography (see the Supporting Information for
details).[13] This structure supports our hypothesis of product
inhibition, because both the alcohol and the amide group are
ideally positioned to render the cyclobutanes excellent
bidentate ligands.
Finally, we turned our attention to alternative functional
groups for enforcing the two-point binding of the radical
intermediates (Scheme 5). Particularly interesting in this
respect are oxazolidinones and morpholine-derived amide,
because both can be additionally manipulated, for example,
through alkylation, or transformed into acids, alcohols,
ketones, or aldehydes[14] in a straightforward manner. Thus,
a large number of functionalized cyclobutanes can in principle
be accessed from the corresponding cyclization products.
Cyclobutane 21 can be obtained in 84% yield as an 89:11
mixture of separable diastereoisomers. Therefore, the use of
oxazolidinones for binding to the cationic catalyst is not only
possible but even results in higher yields of the corresponding
products relative to those obtained when the amides are used;
this is additionally corroborated by the results of 22 and 25.
Notably, for the latter two cases it was necessary to heat the
reaction mixture to reflux to ensure a high conversion into the
desired products 23 and 26. In these cases, the minor
cis isomers were obtained as the lactones 24 and 27. Finally,
both the pyrrolidinone derivative 28 and the morpholine-
derived amide 30 gave the desired cyclobutanes 29 and 31,
respectively. As expected, 31 was formed with complete
diastereoselectivity.
Scheme 3. Mechanistic rationale for the diastereoselectivity of the
templated 4-exo cyclization.
To investigate the general applicability of our concept and
to understand the relative importance of the steric interac-
tions for the diastereoselectivity of the cyclization, we
investigated substrates having different epoxide and amide
substitution (Table 2 and Scheme 4). The presence of n-alkyl
substituents at the epoxide (Table 2, entries 1–4) led to a
slightly decreased diastereoselectivity with the yield of the
products remaining almost unaffected. Introduction of the
bulkier cyclohexyl group results in a low-yielding and
unselective reaction (Table 2, entry 5).
Amide substitution does not appear to be critical
(Scheme 4) as both 17 and 19 are obtained in slightly lower
yields than 2 and with complete diastereoselectivity. The
relative configuration of trans-15 was proven by X-ray
In conclusion, we have devised a novel concept for the
realization of one of the most difficult radical cyclizations
based on the use of our cationic titanocene complexes.
Through binding of both the radical and radical acceptor to
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Communications
Keywords: cyclization · cyclobutane · radicals ·
.
template synthesis · titanium
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Scheme 5. Additional examples of the template-catalyzed 4-exo
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Experimental Section
A typical procedure: In an oven-dried schlenk-flask, under Ar, 5
(48 mg, 100 mmol, 0.200 equiv) and manganese (110 mg, 2.00 mmol,
4.00 equiv) were suspended in THF (5 mL). After the reaction
mixture turned lime-green, 20 (113 mg, 0.500 mmol, 1.00 equiv),
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Received: August 7, 2009
Published online: October 23, 2009
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