Some common features of biologically active compounds
are cyclic, polycyclic, or macrocyclic ring systems, the
presence of H-bond donors and acceptors, and hydropho-
bic regions. Some obvious lead compounds in this regard
are cyclic peptides,6-8 depsipeptides,9 or macrolactones.10
If targeting peptidelike molecules, a departure from
typical R-amino acids is tantamount to a sometimes
substantial synthetic effort. Thus, there is a need for
adapting powerful organic reactions to the synthesis of
building blocks that can replace amino acids in cyclic
peptides. In this paper we show that aldol building blocks
can be fashioned into macrocyclic peptidomimetics.11
The asymmetric aldol reaction is one of the most
important reactions in natural product synthesis because
a new carbon-carbon bond is formed with the simulta-
neous creation of two stereocenters.12 A well-known and
reliable reaction in this context is the Evans aldol
reaction.13 Because this reaction combines an aldehyde
with a carboxylic acid it is predestinated for generating
variability due to the large number of available aldehydes
and acids. In addition, the aldol products can be trans-
formed to other difunctionalized derivatives. We planned
to convert aldol products via Curtius rearrangement to
the corresponding amino alcohols14 and then to combine
them with the typical aldol product, a 3-hydroxy acid. If
the two secondary hydroxy groups are connected to
functional groups that can be used for a cyclization
reaction, macrocyclic compounds with a constrained
conformation should result (Figure 1). In this paper we
show that with allyl ethers a short synthesis of macro-
lactams is possible via ring-closing metathesis.
Syn th esis of Cyclic P ep tid om im etics fr om
Ald ol Bu ild in g Block s
Sanjita Sasmal,† Armin Geyer,‡ and Martin E. Maier*,†
Institut fu¨r Organische Chemie, Universita¨t Tu¨bingen,
Auf der Morgenstelle 18, D-72076 Tu¨bingen, Germany and
Institut fu¨r Organische Chemie, Universita¨t Regensburg,
D-93040 Regensburg, Germany
martin.e.maier@uni-tuebingen.de
Received May 1, 2002
Abstr a ct: Aldol products (3-hydroxy acids) with an allyl-
protected hydroxy group were converted to amino alcohols
by Curtius rearrangement. Combination of the carboxylic
acid with the amino alcohols gave the amides 10. Ring-
closing metathesis led to the 12-membered lactams 12 as
mixtures of E/ Z-isomers. The scheme was also transferred
to the solid-phase. In this case the macrolactams are formed
via cyclorelease. For a pair of E/ Z-isomers the solution
conformation was determined by ROESY spectroscopy.
With the appearance of new targets for the treatment
of diseases, the need for selective small molecules has
increased. One strategy to cope with these challenges is
diversity oriented synthesis of large libraries of com-
pounds.1 In designing such libraries it seems advanta-
geous to follow the so-called “rule of five”.2 The more
classical strategy relies on a structure-based approach
which utilizes biologically active natural products as a
starting point for modifications. Combined with solid-
phase techniques this can lead to small libraries in a
short period of time.3,4 With this approach the likelihood
of finding active molecules is rather high.5 However, it
might be difficult to discover a more active molecule or
to find a new mode of action. Therefore, it might be better
to combine the above-mentioned strategies. Thus, using
rough guiding principles that result from inspecting
natural products might increase the probability for hits.
Using standard conditions (1.2 equiv of Bu2BOTf, 1.3
equiv of EtNiPr2, CH2Cl2, -78 to 0 °C) the aldol products
5 were prepared (Scheme 1). Subsequently, the secondary
(6) For the synthesis of cyclic peptides via rcm, see: (a) Ripka, A.
S.; Bohacek, R. S.; Rich, D. H. Bioorg., Med. Chem. Lett. 1998, 8, 357-
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2000, 65, 6187-6195. (c) Blackwell, H. E.; Sadowsky, J . D.; Howard,
R. J .; Sampson, J . N.; Chao, J . A.; Steinmetz, W. E.; O’Leary, D. J .;
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† Universita¨t Tu¨bingen.
‡ Universita¨t Regensburg.
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10.1021/jo025889b CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/23/2002
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