R. Breinbauer et al.
good selectivity for Suzuki coupling with the iodine func-
tionality. The less reactive triflate leaving group was then re-
acted smoothly by using Cs2CO3 as a base. Having the same
solvent and catalyst in common for both Suzuki coupling re-
actions, we were intrigued by the possibility to perform the
teraryl assembly in a one-pot reaction controlled by the se-
quence of addition of the bases. Indeed, in the case of Ile-
Phe-Ala this proposition worked. However, the 79% yield
of product is accompanied by a considerable amount of ho-
mocoupling and other products. Although careful reaction
optimization might have improved the yield and purity for
this reaction, we found it more opportune to come up with a
flexible approach, which is in accordance with our main ob-
jective of this research: the assembly of a comprehensive li-
brary of teraryl mimetics, which makes it necessary to have
reaction conditions available that should work for any build-
ing block combination. We were pleased to see, that the fol-
lowing in situ two-step synthesis protocol offers a good com-
promise between experimental simplicity and synthetic suc-
cess. In a Schlenk tube, the first Suzuki coupling with the
iodine moiety and the first building block was performed
has emerged as a successful paradigm in this area. Especially
Hamiltonꢀs insight, that the teraryl moiety is an excellent
scaffold to position the i, i+3 (or i+4) and i+7 residues of
a folded a-helix has already been successfully applied into
practice. Our new modular approach for the assembly of
such terphenyls using either our halogen/diazonium or halo-
gen/triflate strategy represents a synthetic bonanzafor the
convenient synthesis of such a-helix mimetics. In contrast to
previous efforts it allows the assembly of teraryls by sequen-
tial coupling of preset building blocks without intermittent
protection or deprotection steps. In fact the teraryl assembly
by sequential Suzuki couplings can be performed by sequen-
tial addition of the boronic acid building blocks for the top
and bottom rings. With only a set of 18 core building blocks
2, 3 and 18 substituted aryl boronic acid derivatives 4, any
representative of the 5670 permutations of a-helix mimetics
featuring the proteinogenic amino acids could be prepared
within a day. We are currently working on the synthesis of
such a comprehensive tool box of building blocks, featuring
all proteinogenic amino acids complemented by some non-
natural ones.[32]
with [PdCl2ACHTUNGTRENNUNG(dppf)]·CH2Cl2 with CsF in 1,2-DME. After com-
plete conversion the reaction mixture was filtered through
silica, concentrated in vacuo, and the crude material was
used in the second Suzuki coupling under similar conditions
but with the second boronic acid building block and Cs2CO3
as base. Using this protocol the Ile-Phe-Ala terphenyl 1d
was produced in 59% overall yield, and the Phe-Leu-Val
terphenyl 1e in 54% overall yield (Table 3).[31]
Experimental Section
General methods, additional information and further experimental proce-
dures are given in the Supporting Information.
Representative procedure for the iodination of phenol derivatives 16 to
the corresponding para-iodo phenol derivatives 17: In a one-neck round-
bottom flask (25 mL) the corresponding phenol derivative 16 (1.0 equiv)
was dissolved in acetic acid and iodine monochloride (ICl; 1.0 equiv) was
added at room temperature. In some cases additional ICl was added to
ensure quantitative conversion. The reaction mixture was quenched with
NaHCO3 solution (100 mL, 0.5m) and the aqueous phase was extracted
with CH2Cl2 (3ꢃ50 mL). The combined organic layers were washed with
Na2S2O3 solution (25%, 3ꢃ100 mL) followed by saturated NaCl solution
(1ꢃ100 mL). After being dried over MgSO4, the solvent was removed
under reduced pressure and the crude product was purified by flash
column chromatography.
Table 3. Synthesized terphenyls 1d,e by using the triflate core units 3c
and 3e.
Representative procedure for synthesis of the triflate derivatives 3 from
the corresponding para-iodo phenol derivatives 17: In a flame-dried and
argon-flushed Schlenk-flask the corresponding para-iodo phenol deriva-
tive 17 (1.0 equiv) was dissolved in pyridine. After cooling the solution to
08C trifluoromethanesulfonic anhydride (Tf2O) was carefully added.
After being stirred for 5 min at 08C, the solution was allowed to warm to
room temperature and stirred until quantitative conversion was detected
by TLC. Et2O (60 mL) was added and the organic phase was washed
with H2O (3ꢃ30 mL) followed by the extraction of the combined aque-
ous layers with Et2O (2ꢃ30 mL). The organic phases were washed with
HCl (1m, 2ꢃ60 mL) and saturated NaCl solution (1ꢃ60 mL), dried over
MgSO4 and concentrated, in vacuo. The crude product was purified by
flash column chromatography.
Entry
1
R1
R2
R3
Compound[a]
Yield [%][b]
59
1d
2
1e
54
[a] R1 represents the i position, R2 the i+3 (or i+4) and R3 the i+7 po-
sition of an a-helix. [b] Yields of isolated products over two steps.
Representative procedure for the synthesis of terphenyls 1d,e by consec-
utive double Suzuki coupling: A flame-dried two-neck round-bottom
flask with argon-inlet was charged with the corresponding boronic acid
Conclusion
derivative
4 (1.0 equiv), CsF (2.0 equiv), and [PdCl2ACHTUNGTNUER(NG dppf)]·CH2Cl2
(5 mol%). After being dried, in vacuo, a solution of trifluoromethanesul-
fonate 3 (1.0 equiv) in absolute, degassed 1,2-DME was added. After ad-
ditional degassing, the reaction mixture was stirred at 808C until full con-
version was detected by TLC. The typically brown suspension was fil-
tered through a pad of SiO2 (3ꢃ2 cm, eluents are denoted) and the fil-
trate was concentrated to dryness by using a rotary evaporator.
The inhibition of protein–protein interactions has become
one of the big challenges and areas of research within drug
discovery. Although this field is still in its nascency, recent
results allow the conclusion that the use of a-helix mimetics
&
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ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
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