Short synthesis of protease inhibitors via modified Passerini condensation of N-Boc-α-aminoaldehydes

Article abstract of DOI:10.1016/S0040-4039(02)00728-1

Extension of the previously reported modification of Passerini multicomponent reaction (involving condensation with N-Boc-α-aminoaldehydes followed by a deprotection-transacylation step) to α-aminoacid derived carboxylic or isocyanide components, allowed the highly convergent and short synthesis of complex peptidomimetic structures, including known potent inhibitors of serine proteases.

Full text of DOI:10.1016/S0040-4039(02)00728-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4067–4069
Short synthesis of protease inhibitors via modified Passerini
condensation of N-Boc-a-aminoaldehydes
Luca Banfi,* Giuseppe Guanti,* Renata Riva, Andrea Basso and Emiliano Calcagno
Dipartimento di Chimica e Chimica Industriale, via Dodecaneso 31, I-16146 Genoa, Italy
Received 28 March 2002; revised 12 April 2002; accepted 15 April 2002
Abstract—Extension of the previously reported modification of Passerini multicomponent reaction (involving condensation with
N-Boc-a-aminoaldehydes followed by a deprotection–transacylation step) to a-aminoacid derived carboxylic or isocyanide
components, allowed the highly convergent and short synthesis of complex peptidomimetic structures, including known potent
inhibitors of serine proteases. © 2002 Elsevier Science Ltd. All rights reserved.
Oligopeptides containing the a-hydroxy-b-aminoamide
or the a-oxo-b-aminoamide structures have demon-
strated in many cases to be very useful as ‘transition-
state analog’ protease inhibitors. In particular, the
a-hydroxy-b-aminoamides seem well suited for aspartic
proteases,1 while the a-oxo-b-hydroxyamides are more
successful for cysteine2 and serine proteases.3. Recently
we4,5 and others6,7 have disclosed a new variation of the
old Passerini multicomponent reaction,8 allowing a
short entry into various members of these two classes of
peptidomimetics. This methodology is based on a
Passerini condensation of N-Boc-a-aminoaldehydes fol-
lowed by smooth deprotection–transacylation to afford
In order to obtain higher oligopeptides and, at the same
time, to further increase the number of diversity factors
in the final products, we have now extended the
methodology to functionalised carboxylic acids and/or
isocyanides derived from a-aminoacids.9 In this way
four or even five factors of diversity may be introduced
in a 3–4 step linear sequence to give 4 or 5-unit
peptidomimetics.
For example, four different inputs may be introduced
in the synthetic scheme by employing a N-Boc-a-
aminoacid as carboxylic component as shown in
Scheme 2.10 After Passerini reaction11 (that took place
without epimerisation at the stereogenic centres of the
aldehyde and of the acid), treatment with CF3CO2H
cleaved both Boc groups. Then, upon basification, the
acyl group migrated exclusively on the aldehyde derived
amino group. The remaining free amine in 6 could be
coupled with another carboxylic acid (the fourth factor
of diversity) to give tetrapeptide 7 in three steps and
with an overall yield of 59% (Scheme 3).
a
three-unit peptidomimetic incorporating an a-
hydroxy-b-aminoamide (Scheme 1). The three units
derive from the three components of the Passerini
reaction.
A similar strategy was employed in the synthesis of
a-oxoamides 1215 and 17,16 known to be potent
inhibitors of two important serine proteases: prolyl
endopeptidase and Cytomegalovirus protease, respec-
tively. In these cases, the synthesis was completed by a
final oxidation with sodium hypochlorite and catalytic
TEMPO radical.17 The synthesis of Cytomegalovirus
protease inhibitor 1718 is particularly noteworthy since
in this case a complex structure formed by five frag-
ments joined trough four amide bonds was prepared
convergently in only three steps and with an overall
yield of 35%.
Scheme 1.
Keywords: Passerini reaction; protease inhibitors; peptidomimetic;
multicomponent reactions; isocyanides; oxoamides.
* Corresponding authors. Tel.: +39-010-3536119; fax: +39-010-
3536118; e-mail: banriv@chimica.unige.it; guanti@chimica.unige.it
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00728-1

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L. Banfi et al. / Tetrahedron Letters 43 (2002) 4067–4069
Scheme 2.
Scheme 3.
Another way to increase the complexity of the a-
oxoamides prepared by our methodology is to employ a
dipeptidic isocyanide, such as compound 1819 (Scheme
4). In this way, a-oxoamide 20, which is the methyl
ester of a known potent inhibitor of prolyl endopepti-
dase,21 could be prepared in three steps and 35% overall
yield. This compound is formed by four different units
joined by amide bonds.
The high convergency of the synthetic pathways shown
in this communication definitely compensates for the
fact that the yields of Passerini condensations, in some
cases, were not as good as when simple monofunction-
alised components were used.4 When employing N-Boc-
a-aminoacids as the carboxylic component, we often
detected the formation of variable amounts of the
corresponding a-hydroxyamides, formally derived from
Scheme 4.

L. Banfi et al. / Tetrahedron Letters 43 (2002) 4067–4069
4069
coupling of the isocyanides with the aldehydes without
inclusion of the carboxylic component. For example,
during the synthesis of 14, the desired adduct 14 was
also accompanied by a 32% yield of the corresponding
a-hydroxyamides.22 Subtle differences in the structure
of the three components seem to be important in deter-
mining the yields. The worst case found so far by us is
represented by the condensation of isocyanide 18 with
alanine). In our hands, no appreciable racemisation was
observed upon chromatography (see Ref. 13). Aldehydes
4, 9 and 19 were prepared from the corresponding (Boc)
aminoacids by reduction with BH3·Me2S (Ref. 14) (62, 94
and 93% yield) followed by Swern oxidation (quantita-
tive).
12. Goel, O. P.; Krolls, U.; Stier, M.; Kesten, S. Org. Synth.
1998, 67, 69–75.
13. Cushman, M.; Oh, Y.; Copeland, T. D.; Oroszlan, S.;
Snyder, S. W. J. Org. Chem. 1991, 56, 4161–4167.
14. Jurczak, J.; Golebiowski, A. Chem. Rev. 1989, 89, 149–
164.
aldehyde 19 and (Boc)-L-valine, that gave the expected
Passerini product (an intermediate for the synthesis of
poststatine24) in only 30% yield. However, simply by
using aldehyde 9 instead of 19, the yield was raised to
an acceptable 62%.
15. Tsuda, M.; Muraoka, Y.; Nagai, M.; Aoyagi, T.;
Takeuchi, T. J. Antibiot. 1996, 49, 909–920.
In conclusion we have shown here that a very concise
and convergent assembly of complex peptidomimetics
containing an a-hydroxyamide or an a-oxoamide unit
can be achieved by using N-Boc-a-aminoacids (as car-
boxylic components) or peptidic isocyanides as sub-
strates in the previously reported variation of Passerini
condensation.4 The utility of this methodology is partic-
ularly evident in the field of protease inhibitors, as
demonstrated by the examples reported here as well as
by the recently published synthesis of a fragment of
cyclotheonamide.7
16. Ogilvie, W.; Bailey, M.; Poupart, M.-A.; Abraham, A.;
Bhavsar, A.; Bonneau, P.; Bordeleau, J.; Bousquet, Y.;
Chabot, C.; Duceppe, J.-S.; Fazal, G.; Goulet, S.; Grand-
Maitre, C.; Guse, I.; Halmos, T.; Lavallee´, P.; Leach, M.;
Malenfant, E.; O’Meara, J.; Plante, R.; Plouffe, C.;
Poirier, M.; Soucy, F.; Yoakim, C.; De´ziel, R. J. Med.
Chem. 1997, 40, 4113–4135.
17. Harbeson, S. L.; Abelleira, S. M.; Akiyama, A.; Barrett,
R., III; Carroll, R. M.; Straub, J. A.; Tkacz, J. N.; Wu,
C.; Musso, G. F. J. Med. Chem. 1994, 37, 2918–2929.
18. Compound 14 was prepared in 74% overall yield from
N-Boc-
THF; (2) Me2NH·HCl, Et3N; (3) H2, Pd/C, iPrOH.
Compound 15 was prepared from -N-Boc-tert-leucine in
L
-aspartic acid a benzyl ester: (1) Et3N, ClCO2Et,
Acknowledgements
L
five steps (54% overall yield): (1) Boc-ON, Et3N, 1,4-
dioxane; (2) BnOH, N-ethyl-N(3-dimethylaminopropyl)-
carbodiimide (EDCI), 4-dimethylaminopyridine, CH2Cl2,
0°C, 80% (two steps); (3) CF3CO2H, CH2Cl2; (4) t-
BuCH2CO2H, N-hydroxybenzotriazole, EDCI, N-
methylmorpholine, CH2Cl2, 75% (two steps); (5) H2,
Pd–C, i-PrOH, 91%.
We wish to thank C.N.R., the University of Genoa,
and M.U.R.S.T. (COFIN 00) for financial assistance,
and Miss Sabrina De Biase for her help in this work.
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1
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