Application of tandem Ugi reaction/ring-closing metathesis in multicomponent synthesis of unsaturated nine-membered lactams

Article abstract of DOI:10.1016/j.tetlet.2003.08.027

A new straightforward entry into unsaturated nine-membered lactams of potential use as external reverse turn inducers was developed. It is based on an Ugi multicomponent reaction using two unsaturated substrates, followed by highly stereoselective ring-cl

Full text of DOI:10.1016/j.tetlet.2003.08.027

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7655–7658
Application of tandem Ugi reaction/ring-closing metathesis in
multicomponent synthesis of unsaturated nine-membered lactams
Luca Banfi,* Andrea Basso, Giuseppe Guanti and Renata Riva
Dipartimento di Chimica e Chimica Industriale, via Dodecaneso 31, I-16146 Genova, Italy
Received 4 July 2003; revised 28 July 2003; accepted 7 August 2003
Abstract—A new straightforward entry into unsaturated nine-membered lactams of potential use as external reverse turn inducers
was developed. It is based on an Ugi multicomponent reaction using two unsaturated substrates, followed by highly stereoselective
ring-closing metathesis (RCM). The synthesis of a nine-membered secondary lactam by RCM is reported for the first time.
© 2003 Elsevier Ltd. All rights reserved.
inducers and decided to explore a new straightforward
entry into these scaffolds by coupling a multicompo-
nent reaction (Ugi-4CR)16 with a ring-closing metathe-
sis (RCM).17 In this way, libraries of compounds of this
type could be accessed in a few steps, introducing three
diversity factors (R1, R2 plus groups different from
methyl in the starting ketone) following the general
strategy depicted in Scheme 1.
The conformational restriction of peptide chains by
attaching them to semirigid scaffolds is an important
strategy toward the development of receptor antago-
nists endowed with higher affinity and selectivity.1
Moreover, this approach leads to valuable information
on the real conformation of the natural ligand. The
scaffolds capable of inducing a reverse-turn in a peptide
backbone attached to it are of particular interest. These
have been referred to as ‘external reverse turn scaf-
folds’.2 Bicyclic lactams3 or monocyclic five- to seven-
membered monocyclic ‘Freidinger’ lactams4 have been
extensively used in the past as external reverse turn
inducers. On the other hand, there are very few exam-
ples in the literature involving mesocyclic lactams.5,6
Due to their higher flexibility, mesocyclic compounds
are expected to be useful as external reverse turn induc-
ers only if some other kind of conformational restric-
tion is present, such as an unsaturation. At the outset
of this work we could only find very few examples
concerning the synthesis of unsaturated nine-membered
lactams in the literature.7,8 None of them, however,
were suited for acting as reverse-turn scaffolds, since
they were lacking the necessary amino and carboxylic
functionalities. Only very recently has Gmeiner
reported the synthesis of potential reverse turn inducers
In this study, we used, as in situ source of the imine 1
or 2, a model ketone, namely 5-hexen-2-one. In the
course of preliminary experiments we found out that by
simply mixing this ketone with an amine, various acids,
and ethyl or t-butyl isocyanoacetate, the desired Ugi
reaction took place, but with very long reaction times
and in some cases in unsatisfactory yields. On the other
hand, the analogous reactions employing preformed
imines 1 or 2 were complete in 1–2 days affording
excellent yields.
based on
a
nine-membered unsaturated tertiary
lactam.9
This prompted us to report our results in this area.
Through preliminary computer-aided conformational
analyses10–15 we devised hexahydroazoninones of gen-
eral formula 6 as highly promising external reverse turn
* Corresponding author. Tel.: +39-010-3536119; fax: +39-010-
3536118; e-mail: banfi@chimica.unige.it
Scheme 1.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.08.027

7656
L. Banfi et al. / Tetrahedron Letters 44 (2003) 7655–7658
Table 1. Results of the tandem Ugi 4-component (U-4CR)/RCM reactions
Entry
R1
R2
R3
U-4CRa
Yield (%)
RCMb
Yield (%)
Product
Product
1
2
3
4
5
6
7
8
9
PhCH2
PhCH2
nBu
PhCH2
nBu
PhCH2
PhCH2
PhCH2
PhCH2
PhCONHCH2
PhCONHCH2
(Boc)NHCH2
(Boc)NHCH2
PhCH2
tBu
Et
Et
Et
Et
Et
Et
tBu
tBu
5a
5b
5c
5d
5e
5f
5g
5h
5i
80c
93c
79d
82d
76d
85d
63d
86c
69c
6a
6b
6c
6d
6e
6f
6g
6h
6i
69
58
42 (55)
45 (65)
26 (39)
43 (51)
40 (52)
46
CH3
(Boc)NHCH2CONHCH2
(Fmoc)NHCH2
(Fmoc)NHCH2CONHCH2
50
a Reactions were carried out for 48–72 h in MeOH or EtOH at room temperature and at 1 M reactant concentration. Yields are of pure isolated
products (50:50 diastereoisomeric mixture).
b Reactions were carried out for 48 h in CH2Cl2 at reflux under Ar at 4 mM concentration, using 0.2 equiv. of Grubbs’ catalyst [benzylidene–
bis(tricyclohexylphosphine)ruthenium dichloride]. Overall yields of the two pure isolated diastereoisomers are reported. Yields in brackets are
calculated taking into account the recovered substrate.
c Reaction carried out in MeOH.
d Reaction carried out in EtOH.
Thus, allyl substituted racemic isocyanoacetates 318 or
419,20 were reacted in MeOH or EtOH21 with two
preformed imines 1 or 2 and various carboxylic acids to
give Ugi adducts 5 in excellent yields.22 The results are
listed in Table 1. It is worth noting that some of the
carboxylic acids employed were protected amino acids
or peptides. No diastereoselection was observed in all
the cases tested so far. The diastereoisomeric ratio was
always 50:50 as determined by NMR. The isomers were
not easily separable at this stage and therefore we
carried out all the subsequent cyclization reactions on
the diastereomeric mixture.
the analogous RCM reaction leading to ten-membered
rings affords E or Z isomers depending on the sub-
stituents and on the double bond position.5,9
At this stage, the two diastereoisomers (cis and trans)
resulting from the nonstereoselective Ugi reaction could
be easily isolated by chromatography23 in nearly all the
cases, the exceptions being Fmoc-containing adducts 6h
and 6i. NOE experiments,24 carried out on the two
diastereoisomers of 6f, demonstrated that the com-
pound with the lower Rf value (petroleum ether/AcOEt
eluents) had the trans configuration. A series of NMR
analogies (1H and 13C)25 indicated that for 6a–e and 6g,
the compounds with lower Rf were trans as well.
By treating these Ugi adducts with Grubbs’ first gener-
ation catalyst in refluxing CH2Cl2, the nine-membered
lactams 6a–i were isolated23 in yields that could be
considered quite good for the closure of a mesocyclic
ring. The isolated by-products were all acyclic com-
pounds derived from intermolecular reactions as indi-
cated by the presence of terminal CHꢀCH2 carbons in
the 13C NMR (DEPT) spectrum. Further lowering the
concentration below 4 mM did not suppress the forma-
tion of these by-products and resulted in lower yields.
These results represent the first examples of cyclization
under RCM conditions of secondary amides to nine-
membered lactams. It is worth noting that the similar
cyclization of secondary amides to afford eight-mem-
bered rings by RCM is reported to be unfeasible.6 An
explanation for this different behavior may be the
preference for anti amide bond conformations in hexa-
hydroazoninones,8 as foreseen by computer-aided con-
formational analysis11 and demonstrated by NOE
experiments.24
In conclusion, we have demonstrated for the first time
the preparation of nine-membered secondary lactams in
moderate to good yields by RCM and that this cycliza-
tion is highly stereoselective with regard to the double
bond configuration. We have also developed a highly
convergent approach to these promising scaffolds,
amenable to the introduction of three diversity factors,
by coupling the Ugi four-component reaction with an
RCM.
At present our research is focussed on the use of
enantiomerically pure 3 and 4 and optically active
protected amino acids or peptides in order to obtain, in
a few convergent steps, scaffolds well suited for the
synthesis of constrained cyclic peptides.
Acknowledgements
These RCMs were found to be highly stereoselective
with regard to double bond configuration. In the crude
mixtures we could detect only two cyclic products,
diastereoisomeric at the two stereogenic centers. The
double bond configuration was unambiguously estab-
lished as Z in several instances by the CHꢀCH coupling
constants (9–10 Hz). This result was not fully expected:
We wish to thank the University of Genoa, and
MURST (COFIN 00, COFIN 02) for financial assis-
tance, Professor Carlo Scolastico for his crucial advice,
Professor Beat Ernst and Samuel Schmid for help in
conformational analyses, and Silvia Anthoine-Dietrich
for her precious collaboration to this work.

L. Banfi et al. / Tetrahedron Letters 44 (2003) 7655–7658
7657
References
11. Conformational analyses were carried out at the Institute
of Molecular Pharmacy, Pharmacenter of the University
of Basel, and would have not been possible without the
precious collaboration of Professor Beat Ernst and
Samuel Schmid. They have been performed on a Silicon
Graphics O2 console, using the program MacroModel,12
version 5.0. TNCG (Truncated Newton Conjugate Gradi-
ent)13 and Amber* force field (Amber all-atom force
field) have been used for the minimization steps, while
unconstrained Monte Carlo/energy minimisation (MC/
EM)14 has been applied for the conformational search
(ring closures have been defined for each ring, when these
were not automatically defined). At least 2,000 conforma-
tions were generated for each analysis, only those with
energy not exceeding 50 kJ/mol from the global minimum
being taken into consideration. Each conformation was
minimized (500 iterations) and only those having a gradi-
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18. Isocyanide 3 was prepared from commercially available
diethyl formamido malonate: (a) NaH, DMF, rt, 95%;
(b) 0.13 M NaOH in EtOH, rt; (c) dioxane, reflux, 79%;
(d) POCl3, Et3N, CH2Cl2, −30°C, 92%.
19. Isocyanide 4 was prepared from t-butyl isocyanoacetate
as described.20 In our hands the yields were not higher
than 40%.
20. Scho¨llkopf, U.; Hoppe, D.; Jentsch, R. Chem. Ber. 1975,
108, 1580–1592.
21. In some cases by using MeOH and isocyanide 3 we
observed various degrees of transesterification. Thus we
now prefer to use EtOH for reactions involving 3.
22. All new compounds were fully characterized by 1H and
13C NMR, IR, GC–MS (when possible) and elemental
analysis.
23. While the two diastereoisomers were usually well sepa-
rated by silica gel chromatography using petroleum ether/
AcOEt eluents (with the exceptions of 6h and 6i),
complete removal of intermolecular products was in some
cases troublesome and required 2–3 subsequent chro-
matographies with different eluents.
10. Conformational analysis11 carried out on compound 7
(cis isomer) in chloroform showed that in 70% of the
conformations not exceeding 12.57 kJ/mol from the
global minimum, a hydrogen bond between Oai and
Nai+3, typical of a reverse turn, was present. The remain-
ing conformations had either a hydrogen bond between
Oai and Nai+2 (10%) or between Oai+1 and Nai+3 (20%).
In water the percentage of considered conformations
characterized by a hydrogen bond decreased from 100 to
55%, but 44% of them still had the H-bond between Oai
and Nai+3. The b virtual dihedral angle (CaiꢁCai+1ꢁCai+
2ꢁNi+3) was optimal for a reverse turn in 67 or 60% of the
conformations considered, respectively, in water and
chloroform. For the trans epimer of 7 the situation was
far less favorable. No considered conformation possess-
ing a H-bond between Oai and Nai+3 was found. The
epimer of 7 also turned out to be generally less stable and
more flexible than 7.
24. The trans isomer of 6f showed a remarkable 20% NOE
on the NH when irradiating the CH3 bonded at C-3. This
is clearly possible only for this diastereoisomer and only
if the cyclic amide is in an anti conformation. On the

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L. Banfi et al. / Tetrahedron Letters 44 (2003) 7655–7658
Chem3D) preferred conformations.
other hand, the cis epimer of 6f showed a 10% NOE on
one of the two H-4 (irradiating the same methyl), as well
as a 3% NOE on the NH by irradiating the aromatic
protons and a 2% NOE on CH3CO irradiating the NH.
Also these latter NOEs seem possible only if the amide
conformation is anti. The CO2R4 group prefers a pseudo-
equatorial position in both epimers, as demonstrated by
the high J (9–10 Hz) between NH and CHꢁN. Thus in
the cis compound the methyl group is pseudo-axial and
lies at a close distance with one of the H-4. All these
results fit well with the expected (Macromodel and
25. In the 1H NMR spectra, the CH3 bonded at C-3 res-
onates at 1.43–1.49 in trans isomers and at 1.65–1.70 in
the cis counterparts. In the 13C C-5: trans: 32.91–33.68;
cis: 29.60–30.92. C-6: trans: 124.02–124.19; cis: 122.55–
122.85. C-7: trans: 134.21–134.46; cis: 134.90–135.35.
The methyl at C-3 is always upfield for trans isomers by
0.5–1.75 ppm. C-4 is always downfield for trans isomers.
C-8 is always upfield for trans isomers by 0.60–0.93 ppm.
C-9 is always downfield for trans isomers by 0.42–0.55
ppm.