Diversity-oriented synthesis of polycyclic scaffolds by modification of an anodic product derived from 2,4-dimethylphenol

Article abstract of DOI:10.1002/anie.201006637

Like a Swiss army knife: The pentacycle shown, which results from the anodic oxidation of 2,4-dimethylphenol, displays a wealth of potential reactivity. Depending on the applied reaction conditions a variey of polycyclic architectures are obtained with impressive stereo-, regio-, and chemoselectivity.

Full text of DOI:10.1002/anie.201006637

DOI: 10.1002/anie.201006637
Scaffold Diversity
Diversity-Oriented Synthesis of Polycyclic Scaffolds by Modification of
an Anodic Product Derived from 2,4-Dimethylphenol**
Joaquin Barjau, Gregor Schnakenburg, and Siegfried R. Waldvogel*
One of the biggest challenges facing the biologists and
chemists is understanding the mechanisms that control
biological processes.[1] The structures of the chemical com-
pounds involved in these mechanisms determine their role,
for example, as drugs or as proteins with given functions. To
understand the role a particular compound plays in a
biological process, its chemical profile must be determined.
Screening experiments carried out with compound libraries
are used to search for the discrete target displaying the
desired properties. In this search, libraries of compounds
showing a broader diversity of frameworks span larger tracts
of biologically relevant chemical space,[2] making it easier to
identify lead molecules.[3] Organic chemists use a limited
range of functional groups for synthesizing compounds based
on already known architectures;[4] hence generating structural
complexity and diversity is crucial in the creation of
compound collections for biological screening.[5] The syn-
thesis of target molecules and medicinal chemistry in general
cover a limited chemical space, since at most only a diversity
of functional groups is possible. For this reason a concept with
more structural flexibility is needed. Diversity-oriented syn-
thesis (DOS) focuses on the generation of structurally diverse
scaffolds in the fewest possible steps.[6] This new field of
organic chemistry covers a broader chemical space by using
diversity-generating reactions to achieve high substitutional,
stereochemical, and skeletal diversity. DOS can be achieved
by biomimetic transformations[7] and functional-group pair-
ing,[8] as well as by convergent,[9] domino,[10] and cascade[11]
approaches and multicomponent reactions.[12] In these
approaches the particular emphasis is on innovations that
allow skeleton modification.[13] Recently, Moeller and co-
workers developed a electrochemical protocol for the syn-
thesis of addressable libraries as platforms for biological
assays on microelectrode arrays.[14] Electrochemical reactions
have been used as the key step in the synthesis of complex
molecules.[15] Herein, we report a new electrochemically
based DOS protocol, in which the electrooxidation of 2,4-
dimethylphenol is the key reaction for the complexity-
generating strategy.
The electrooxidation of 2,4-dimethylphenol (1) on Pt
electrodes using Ba(OH)2·8H2O in methanol as electrolyte
affords compound 2 (Scheme 1).[16] This dehydrotetramer of
Scheme 1. Electrooxidation leading to the key intermediate 2.
2,4-dimethylphenol can be obtained in large quantities (up to
23 g per run) and is easily isolated since it precipitates during
electrolysis in an undivided cell. The formation of 2 takes
place with exclusive diastereoselectivity; most probably the
divalent cation Ba2+ brings together the initially formed
Pummerer ketone derivative and another unit of 1 in a
defined orientation.[17] Scaffold 2 shows a range of function-
alities for subsequent diversity-generating reactions
(Scheme 2). Similar to a Swiss Army knife, wherein a
simple action provides a distinct function or tool, simple
transformations applied to the richly functionalized inter-
mediate 2 led to 14 compounds with 11 different scaffolds in
good to excellent yield. The optimized reactions provide a
library of novel polycyclic architectures. By manipulating the
reaction conditions we could create molecules with alterna-
tive scaffolds, the cornerstone of diversity-oriented synthesis,
and achieve stereo-, regio-, and chemoselectivity control.
When the anodically produced key intermediate 2 is
treated either thermally,[16] or more efficiently with acid, the
spiropentacycle 3 is obtained exclusively.[17] In the cationic
intermediate a stabilizing secondary orbital interaction might
exist between the lone pairs of electrons on the oxygen atoms
and the empty orbital (Scheme 3). This interaction suggests a
late transition state. Most remarkably, blocking the hydroxy
group of the hemiketal moiety of 2 with acid-labile groups
greatly influences the course of the reaction. The silylation
reaction can be performed under standard conditions, provid-
ing, for example, the O-TIPS-protected 4c in good yield
(86%). It is noteworthy that the hemiketal is not opened up.
Treatment of these silylated substrates with Lewis acids
results in the preferential formation of 5, an epimer of 3 in
which the spiro center is inverted (Scheme 2). The acid
lability of the silyl groups is directly reflected in the 3/5 ratio
[*] J. Barjau, Prof. Dr. S. R. Waldvogel
Institute for Organic Chemistry, University of Mainz
Duesbergweg 10–14, 55128 Mainz (Germany)
E-mail: Waldvogel@uni-mainz.de
Dr. G. Schnakenburg
X-ray Analysis Department
Institute for Inorganic Chemistry, University of Bonn (Germany)
[**] J.B. thanks the DAAD-La Caixa program for a fellowship. Financial
support from the SFB 813 “Chemistry at Spin Centers” (DFG) is
highly appreciated.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201006637.
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Scheme 2. Diversity-oriented strategy. Reagents and conditions: a) conc. H2SO4, toluene, RT, 4 h, 75%; b) 2,4-lutidine (4 equiv), TIPSOTf
(3 equiv), CH2Cl2, RT, 7 days, 86%; c) BF3·Et2O (3.5 equiv), CH2Cl2, RT, 12 h, 62%; d) Et3SiH (2 equiv), TFA (2 equiv), CH2Cl2, RT, 24 h, 80%;
e) SOCl2 (1.5 equiv) CH2Cl2, RT, 7 days, 59%; f) NaCN (4 equiv), CH3CN, 808C, 24 h, 82%; g) PvCl (4 equiv), DMAP (1%), NEt3 (4 equiv), CH2Cl2,
RT, 2 days, 81%; h) LiAlH4 (1 equiv), THF, 08C to RT, 24 h, 76%; i) NH4F (4 equiv), CH3CN, 808C, 24 h, 67%; j) thiophenol (2 equiv), BF3·Et2O
(2 equiv), CH2Cl2, À788C to RT, 99%; k) anisole (2 equiv), BF3·Et2O (1 equiv), CH2Cl2, À788C to RT, 50%; l) 3,5-dimethoxyphenol (1.1 equiv),
BF3·Et2O (4 equiv), CH2Cl2, À788C to RT, 94%. TIPSOTf=triisopropylsilyl triflate, TFA=trifluoroacetic acid, PvCl=pivaloyl chloride, DMAP=4-
dimethylaminopyridine.
(Table 1). The trimethylsilyl-protected substrate 4a provides
a mixture of 3 and 5 in a 30:70 ratio (Table 1, entry 1). When
the silyl groups are bulkier, the yield of 5 increases and the
transformations are significantly cleaner (Table 1, entries 2
and 3).
A mechanistic rationale is given in Scheme 3. Liberation
of 2,4-dimethylphenol from 4 generates the cationic species I.
Repulsion of the lone pairs of the oxygen functionalities paves
the way to 3. When silyl-protected substrates are used, the
rearrangement of cation II is disfavored on the Re side and
consequently, the less sterically demanding pathway leads to
5. The stereochemical course of the Wagner–Meerwein
rearrangement can be efficiently altered by the use of a
proton equivalent. The rearrangement of the silylated species
occurs in almost 70% total yield (Table 1). The bulk of the
silyl moieties directs the skeletal rearrangement since cleav-
age of the silyl moiety seems to be the final step. Complete
stereochemical reversal and exclusive formation of 5 is
probably not possible, since the desilylation seems to occur
under electrophilic conditions to some extent prior to the
rearrangement. When typical conditions for ionic hydro-
genation are applied to 2,[18] dibenzofuran 6 is formed as the
sole product by reduction of the benzylic position, elimination
of water, ring opening, and 1,2-shift. Thus 6 is obtained from 1
in only two simple preparative steps (a mechanistic rationale
is given in the Supporting Information).
Table 1: Diastereoselectivity in the formation of 3/5.
Treatment of key intermediate 2 with thionyl chloride
leads to the demethylation of a quaternary carbon atom of the
central carbocycle. A sequence of elimination reactions
results in the pentacyclic heteroaromatic system 7 (a mech-
anistic rationale is given in the Supporting Information).
Treatment of 2 with cyanide as a potent nucleophile alters the
connectivity of the polycyclic scaffold and provides 8 in 82%
yield. The mechanistic proposal includes ring opening of the
Entry
R
3/5
Yield of 5 [%]
1
2
3
Si(CH3)3 (4a)
Si(CH2CH3)3 (4b)
Si(CH(CH3)2)3 (4c)
30:70
25:75
10:90
47
53
62
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When anisole is used as a carbon nucleophile, the arylation
reaction occurs exclusively at the 4-position of anisole and
product 13 is obtained. This particular scaffold is remarkably
similar to the naturally occurring rocaglamide (see the
Supporting Information),
a secondary metabolite from
Scheme 3. Diastereoselective formation of 3 and 5. Pathway for the
intermediate starting from 2 (top) and reaction course of silylated
species (bottom).
hemiketal, elimination to the a,b-unsaturated system, and
subsequent ring closure (see the Supporting Information).
The hemiketal portion of 2 can be modified under mild
conditions without affecting the rest of the structure. Esterifi-
cation with pivaloyl chloride provides cyclohexenone 9 in
81% yield. Treatment with LiAlH4 gives the highly function-
alized cyclohexenol 10 as a single diastereomer. In reactions
with good nucleophiles the 2,4-dimethylphenoxy substituent
of 2 can be replaced. Subjecting 2 to ammonium fluoride in
acetonitrile installs the amino group on a benzylic position
and simultaneously cleaves the hemiketal. To our knowledge
no similar conversion has been reported. The excellent
hydrogen-bond-donating capabilities of the phenolic moiety
leads to an intramolecular hydrogen bond to the amino
function while liberating the central cyclohexenone 11.
Replacement of the oxygen-bound aryl moiety in 2 by thiols
requires low temperatures. Under these conditions 12 is
formed quantitatively, whereas at ambient temperatures
redox transformations lead to diaryl disulfides and benzo-
furan 6. At low temperatures Friedel–Crafts chemistry is
accessible while the pentacyclic architecture is conserved.
Figure 1. X-ray crystal structures of the novel polycycles. Dark gray C,
light gray H, blue N, red O, yellow S, turquoise Si.
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À
additional hydroxy group ortho to the newly formed C C
bond, the propellane derivative 14 is produced in excellent
yield.
The structural assignment of the obtained products was
challenging since the polycyclic products show suitable but
not unequivocal NMR data. For almost all new scaffolds, X-
ray analyses of suitable single crystals could be performed.
Consequently, the structural elucidation was feasible. Molec-
ular structures of these novel scaffolds based on X-ray data
are depicted in Figure 1. Further details on the individual
architectures and crystal packing are provided in the Sup-
porting Information.
In conclusion, we have found a simple way to create
molecular complexity by anodic oxidation of 2,4-dimethyl-
phenol. The resuling dehydrotetramer 2 can be transformed
into an variety of scaffolds depending on the applied reaction
conditions. In our approach, the polycyclic architectures can
be prepared in two or three steps from 2,4-dimethylphenol
with almost exclusive selectivity and in reasonable yields.
Skeleton rearrangements are induced at higher temperatures,
whereas lower temperatures allow manipulations at the
periphery. Several of the molecular architectures obtained
are similar to known natural products (see the Supporting
Information). Polycyclic phenol oxidation products with
similar complexity may also occur during the “oxidative
burst”, a defense mechanism of plants against fungal infec-
tion.[22] In this oxidation coniferyl alcohol is randomly coupled
by reaction with reactive oxygen species.[23] Consequently, our
polycyclic compounds might have antifungal potential. The
biological profile of these structures will be reported in due
course.
Received: October 22, 2010
Published online: January 14, 2011
Keywords: diversity-oriented synthesis · electrochemistry ·
.
oxidation · phenols · polycyclic compounds
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