Highly modular construction of differently substituted dihydrodibenzo[a,c] cycloheptenes: Fast and efficient access to derivatives of 2,2′-cyclo-7, 8′-neolignans

Article abstract of DOI:10.1002/anie.200353597

Tying the knot: Two aryl units are linked in a one-pot reaction. In a subsequent MoCl₅-mediated oxidative cyclization dihydrodibenzo[a,c] cycloheptenes are provided in excellent yields and an unusually broad range of functional groups are toler

Full text of DOI:10.1002/anie.200353597

Communications
Cyclizations
Highly Modular Construction of Differently
Substituted Dihydrodibenzo[a,c]cycloheptenes:
Fast and Efficient Access to Derivatives of
2,2’-Cyclo-7,8’-neolignans**
Beate Kramer and Siegfried R. Waldvogel*
Dedicated to Professor Julius Rebek, Jr.
on the occasion of his 60th birthday
Although cyclolignans containing seven-membered carbo-
cycles, like colchinol derivatives, inhibit the polymerization of
tubulin in vitro, they have received scant attention in the
[*] B. Kramer, Dr. S. R. Waldvogel
Organisch-Chemisches Institut
Westfälische Wilhelms-Universität Münster
Corrensstrasse 40, 48149 Münster (Germany)
Fax:(+49)251-83-39772
E-mail: waldvog@uni-muenster.de
[**] This work was supported by the International Graduation College
“Template-Directed Chemical Synthesis” with a stipend for B.K.
Generous donations ofchemicals by H. C. Starck (Goslar, Germany)
and Wacker AG (Munich, Germany) are gratefully acknowledged.
We particularly thank Prof. Dr. Dieter Hoppe for fruitful discussions
and support.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200353597
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past.[1] Earlier strategies started with the biaryl synthesis
developed by Meyers and yielded the seven-membered ring
system after a multistep sequence.[2] Because of the many
steps and the low overall yields, this pathway is less attractive
for the construction of analogues and natural products of the
metasequirin B series. Spectroscopic, crystallographic, and
theoretical investigations indicate that 2,2’-cyclo-7,8’-neolig-
nans are comparable to their corresponding eight-membered-
ring derivatives, which exhibit a preferential twist-boat-chair
conformation, in terms of their structure and biological
activity.[3] Therefore, easily accessible molecules from this
class of 2,2’-cycloneolignans may serve as surrogates for the
interesting eight-membered lignans.
We report an efficient and highly modular route to
dihydrodibenzo[a,c]cycloheptenes 6. Simple and readily
available components like the appropriately substituted
benzyl halides, benzaldehydes, phosphonium salts, and phos-
phonates were used as starting materials. The reaction
sequence of the one-pot procedure commenced with the
alkylation of the deprotonated phosphorus reagent employ-
ing benzyl halides (Scheme 1). Base was added again, and the
Table 1: Results ofthe alkylation/Wittig oleinfation sequence and
subsequent hydrogenation.
Entry R1
2
3
5
Yield [%]
1
2
3
4
5
6
7
CH3
5a
74
CH3
CH3
CH3
CH3
CH3
CH3
5b
5c
5d
5e
5 f
5g
73
75
35
56
64
43
8
9
CH3
5h
5i
51
72
Scheme 1. a) THF, 08C, nBuLi, 2 h; then 2, 08C, 2 h; then nBuLi, 08C,
2 h; then 3, 15 h, RT; b) THF, Pd/C, H2, 1 atm, 10 h, RT; 5d: THF,
PtO2, H2, 1 atm, 10 h, RT; 5e: TFA, Et3SiH, CH2Cl2, 10 h, RT; c) CH2Cl2,
MoCl5, TiCl4. RT=room temperature, TFA=trifluoroacetic acid.
COOEt[a]
[a] Triethyl phosphonoacetate was employed instead ofthe phosphoni-
um salt 1.
subsequent Wittig reaction with benzaldehyde derivatives
resulted in an isolable mixture of olefins 4, in which all three
components are properly connected. In the succeeding
hydrogenation with palladium on charcoal the reaction
mixture could be used directly, but it was beneficial to
remove the salts and triphenylphosphane oxide.[4] In the case
of the iodo-substituted substrate 4e dehalogenation and
deactivation of the catalyst could be avoided when the
double bond was reduced by treatment with triethylsilane in
trifluoroacetic acid,[5] whereas the reduction of the bromo
derivative 4d succeeded with the Adams catalyst. All hydro-
genations proceeded quantitatively and provided the analyti-
cally pure 1,3-diarylpropanes.[6]
with the phosphonoacetate,[9] and the subsequent Horner
olefination was performed with sodium hydride in toluene.
Toxic thallium or vanadium reagents are often applied for
the intramolecular coupling reaction of electron-rich aryl
groups.[10] The transformation is much better with either
hypervalent iodine systems[11] or the biocompatible MoCl5. If
the latter reagent is used, the substrate must have a 1,2-
dialkoxy substitution pattern for the dehydrodimerization
reaction to succeed.[12] The synthetic power of MoCl5 in the
oxidative cyclization reaction was demonstrated in the con-
struction of the 2,2’-cyclolignans (eight-membered-ring sys-
tems), which proceeded in the moderate yields typical for this
class of compounds.[13] The addition of Lewis acids like TiCl4
enhance the synthetic potential of MoCl5 significantly.[14]
Employing benzyl chlorides[7] for the alkylation of 1 gave
lower yields for 5d–h, whereas the corresponding benzyl
bromides[8] always provided better results (see Table 1,
entries 1–3). The first benzyl moiety could also be introduced
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Table 2: Results ofthe MoCl 5-mediated oxidative coupling reaction.
In contrast to the synthesis of eight-membered lignans, the
oxidative conversion of the 1,3-diarylpropanes using MoCl5/
TiCl4 reagent mixtures gave the corresponding seven-mem-
bered ring systems in excellent yields, and the reaction
tolerated a broad range of functional groups. The construction
of the seven-membered carbocycle 6a was realized in good
yields. Previous procedures for the preparation of similar
compounds with thallium reagents gave substantially lower
yields.[15] Surprisingly, the oxidative coupling reaction provid-
ing the less electron-rich trimethoxy derivative 6b was
accomplished quantitatively. Even a nonactivated phenyl
moiety was successfully subjected to the oxidative cyclization
process (see Table 2, entry 3). Increasing the amount of the
reagent did not lead to better results for the desired product
but rather the formation of a dimeric species.[16] The MoCl5-
mediated oxidative coupling reaction tolerated the valuable
bromo and iodo substituents,[17] which are handles for
subsequent modification of the cyclized products by tran-
sition-metal-catalyzed reactions. Very electron-rich biphenyl
moieties equipped with six methoxy groups (6 f) are found in
many natural products and were obtained in almost quanti-
tative yield by this methodology (see Table 2, entry 6). The
reaction conditions of the MoCl5-mediated transformation
were compatible with a variety of different protective groups
for the phenolic oxygen.[18] When a triisopropylsilyl group was
used, some protolytic desilylation occurred (see Table 2,
entry 7). Homogeneous materials in over 90% yield were
obtained either by subsequent resilylation or by deprotection
of the crude product. Substrates containing benzodioxole
moieties could be cyclized to provide the desired compound
6h in impressive yield despite the oxidation-sensitive meth-
ylene group.
The reaction of 5i with the oxidizing agent was signifi-
cantly slower, since the electrophilic metal center, which
typically binds to the methoxy groups of the substrate, may
coordinate intramolecularly to the ester moiety. Prolonged
reaction times at room temperature also facilitated almost
complete cyclization of 5i to give the seven-membered-ring
system 6i.
We have described the first highly modular construction
of dihydrodibenzo[a,c]cycloheptenes 6. Simple and inexpen-
sive building blocks were connected successfully and effi-
ciently in a one-pot procedure, which was followed by an
oxidative cyclization reaction. The dehydrodimerization reac-
tion was accomplished with MoCl5/TiCl4 reagent mixtures in
almost quantitative yield, and it tolerated a broad variety of
functional groups. This route for the construction of such
dihydrodibenzo[a,c]cycloheptenes is the most efficient strat-
egy to date with overall yields of up to 72%.
Entry Starting Reaction
material conditions
Product
Yield [%]
08C,
40 min
1
5a
6a
87
08C,
25 min
2
3
5b
5c
6b
6c
99
56
08C,
30 min
08C,
30 min
4
5
6
7
8
9
5d
5e
5 f
5g
5h
5i
6d
6e
6 f
6g
6h
6i
95
92
95
À58C,
5 min
08C,
50 min
À258C,
57
20 min
(+35)[a]
08C,
20 min
87
96
258C,
3.5 h
[a] The amount ofdesilylated product isolated is given in parentheses.
Received: December 22, 2003 [Z53597]
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[2] O. BoyØ, A. Brossi, H. J. C. Yeh, E. Hamel, B. Wegrzynski, V.
Toome, Can. J. Chem. 1992, 70, 1237 – 1249, and references
therein.
À
Keywords: biaryls · C C coupling · cyclization · lignans ·
.
molybdenum
[3] J.-Y. SancØau, R. Dhal, E. Brown, Tetrahedron 1994, 50, 3363 –
3380, and references therein.
[4] The triphenylphosphane oxide in the reaction mixture has a high
affinity to the heterogeneous catalyst and slows down the
hydrogenation significantly.
[1] D. F. Tang-Wai, A. Brossi, L. D. Arnold, P. Gros, Heterocycles
1994, 39, 385 – 404; O. BoyØ, Y. Itoh, A. Brossi, Helv. Chim. Acta
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Chemie
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651.
[11] H. Hamamoto, G. Anilkumar, H. Tohma, Y. Kita, Chem.
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[6] All spectroscopic data correspond to the anticipated structures
and correct elemental analyses demonstrate the purity of the
obtained compounds (C Æ 0.4%, H Æ 0.3%).
[12] S. R. Waldvogel, Synlett 2002, 622 – 624.
[13] B. Kramer, A. Averhoff, S. R. Waldvogel, Angew. Chem. 2002,
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[7] Owing to the ease in handling and stability, benzyl chlorides are
recommended despite the lower yields. Preparation in analogy
to: S. J. Howell, N. Spencer, D. Philp, Tetrahedron 2001, 57,
4945 – 4954.
[15] P. Magnus, J. Schultz, T. Gallagher, Chem. Commun. 1984, 1179 –
1180.
[8] Preparation of the benzyl bromides: R. E. tenBrink, J. M.
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[9] R. S. Compagnone, A. Suꢀrez, Synth. Commun. 1992, 22, 3041 –
3051.
[16] When 2.1 equiv MoCl5/TiCl4 was applied, a dimer containing the
3,3’,4,4’-tetramethoxybiphenyl moiety was isolated in 52% yield.
[17] S. R. Waldvogel, E. Aits, C. Holst, R. Frꢁhlich, Chem. Commun.
2002, 1278 – 1279.
[10] Review: G. Lessene, K. S. Feldman in Modern Arene Chemistry
(Ed: D. Astruc), Wiley-VCH, Weinheim, 2002, pp. 479 – 535.
[18] B. Kramer, R. Frꢁhlich, K. Bergander, S. R. Waldvogel, Syn-
thesis 2003, 91 – 96.
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