Elaboration of peptidomimetics derived from a PADAM approach: Synthesis of polyfunctionalised 2(1H)-pyrazinones via an unexpected aromatisation

Article abstract of DOI:10.1055/s-0030-1260807

When the PADAM (Passerini reaction-amine deprotection-acyl migration) strategy is applied to N-Boc amino acids, the resulting β-acylamino- α-hydroxyamides can be elaborated by secondary-alcohol oxidation, Boc deprotection, and intramolecular cyclisation.

Full text of DOI:10.1055/s-0030-1260807

LETTER
2009
Elaboration of Peptidomimetics Derived from a PADAM Approach: Synthesis
of Polyfunctionalised 2(1H)-Pyrazinones via an Unexpected Aromatisation
S
ynthesis of Polyf
n
unctionalise
d
d
2(1
H
)
-Pyraz
r
inones ea Basso,* Luca Banfi, Giuseppe Guanti, Renata Riva, Paolo Tosatti1
Dipartimento di Chimica e Chimica Industriale, Università di Genova, via Dodecaneso 31, 16146 Genova, Italy
Fax +39(010)3536118; E-mail: andrea.basso@unige.it
Received 4 April 2011
Dedicated to Professor Alfredo Ricci on the occasion of his retirement
Hoping to further expand the scope of the strategy out-
Abstract: When the PADAM (Passerini reaction–amine deprotec-
tion–acyl migration) strategy is applied to N-Boc amino acids, the
resulting b-acylamino-a-hydroxyamides can be elaborated by sec-
ondary-alcohol oxidation, Boc deprotection, and intramolecular
lined in Scheme 1, we envisaged that the use of readily
available N-protected a-amino acids as the carboxylic
component of the Passerini reaction could give access to
cyclisation. When TFA is employed to cleave the Boc group a spon- interesting intermediates 3 to be used for the preparation
of heterocyclic scaffolds 4 as depicted in Scheme 2.9
taneous aromatisation to 2(1H)-pyrazinones is observed.
Key words: Passerini multicomponent reaction, isocyanides, het-
erocycles, ring closure, protecting groups, aromatisation
PG1
HN
R1
R2
O
NHPG2
CHO
O
R2
O
N
+
Multicomponent reactions (MCR) are a valuable tool for
the expeditious synthesis of complex molecules with mul-
tiple points of diversity.2 Among the plethora of method-
ologies developed over the years, the MCR based on the
use of isocyanides3 has played an important role in either
target- and diversity-oriented synthesis. Of particular in-
terest is the use of polyfunctionalised components that al-
low elaboration of postcondensation intermediates and
rapid generation of skeletally and stereochemically di-
verse heterocyclic scaffolds.4 One intriguing example of
such general strategy has been developed in our group ex-
ploiting the following series of transformations: 1) Passe-
rini reaction using an N-protected a-amino aldehyde, a
carboxylic acid, and an isocyanide, 2) amine deprotection
of intermediate 1, and 3) intramolecular acyl migration to
final a-acylamino amide 2 (Scheme 1).5 This reaction se-
quence, often referred to as PADAM strategy, has been
used by us6 and others7 for the preparation of peptidomi-
metics and has also been recently slightly modified to as-
semble a combinatorial library of oxazolines.8
NHR3
PG2
NH
O
HN
R2
R1
NHR3
N
H
R1
CO2H
OH
3
+
4
R3NC
Scheme 2 Proposed use of N-protected amino acids for the
PADAM strategy
We started our investigations preparing N-Fmoc-protect-
ed amino aldehydes 7a–c from commercially available
amino acids or amino alcohols as reported in Scheme 3.10
Aldehydes 7 were then reacted with a variety of isocya-
nides and N-protected a-amino acids and subsequently
treated with diethylamine to cleave the Fmoc group and
allow the intramolecular acyl migration. We wanted the
protecting group on the amine coming from the carboxylic
component (PG2 in Scheme 2) to be orthogonal to the
Fmoc, thus we chose to exploit readily available N-Boc-
and N-Cbz-protected L-amino acids (Table 1).
PG
MeNHOMe⋅HCl
NH
PG
DCC, HOBt
R2
R2
Et3N
LiAlH4, Et2O
–78 °C
NH
O
R2
R2
R1
CHO
CH2Cl2, r.t.
R1
R1
NHR3
R2
R1
N
R1
O
NH
O
N
CO2H
+
N
O
N
O
R2CO2H
+
R1
NHR3
Fmoc
5a–b
Fmoc O
Fmoc O
7a–b
OH
O
5–7a, R1 = H, R2 = Bn
5–7b, R1, R2 = -(CH2)3-
R3NC
6a, 98%
6b, 95%
7a, 80%
7b, 35%
1
2
Scheme 1 The PADAM strategy featuring a Passerini reaction with
an N-protected amino aldehyde followed by amine deprotection and
in situ acyl migration
FmocCl, DIPEA
CH2Cl2, r.t.
Swern
oxidation
O
OH
OH
N
N
N
H
Fmoc
Fmoc
5c
6c, 93%
7c, 99%
SYNLETT 2011, No. 14, pp 2009–2012
Advanced online publication: 10.08.2011
x
x
.x
x
.2
0
1
1
Scheme 3 Synthesis of N-Fmoc-protected amino aldehydes
DOI: 10.1055/s-0030-1260807; Art ID: S02811ST
© Georg Thieme Verlag Stuttgart · New York

2010
A. Basso et al.
LETTER
Table 1 Use of N-Fmoc-Protected Amino Aldehydes and N-Protected Amino Acids for the Proposed PADAM Strategya
Fmoc
R1
O
R3
O
NHPG
N
O
R3
a
b
Fmoc
R1
R1
N
R2
NHR4
O
N
R4NC
O
+
+
CO2H
PGHN
R2
7a–c
CHO
R2
NHR4
R3
OH
PGHN
8–14
15–21
Entry
7
PG
R3
R4
Yield of 8–14 (%) Yield of 15–21 (%)
1
2
3
4
5
6
7
(S)-7a
Cbz
Cbz
Boc
Boc
Boc
Boc
Boc
i-Pr
Bn
n-Bu
n-Bu
n-Bu
n-Bu
t-Bu
n-Bu
t-Bu
8 95
9 93
15 65
16 68
17 81
18 92
19 80
20 92
21 88
(S)-7a
(S)-7a
(S)-7a
(S)-7a
(S)-7b
( )-7c
i-Pr
Me
Me
Me
i-Pr
10 92
11 79
12 75
13 99
14 96
a Reaction conditions: a) N-Fmoc-amino aldehyde (1.0 equiv), acid (1.1 equiv), and isocyanide (1.1 equiv) in CH2Cl2 for 18 h at r.t.; b) 8–14 in
a CH2Cl2–Et2NH (4:1) mixture for 18 h at r.t.
The multicomponent reaction proceeded smoothly giving razinones of general formula 4. To our surprise, Cbz re-
the desired products in good to excellent yield. No sub- moval under standard hydrogenation conditions only
stantial difference in reactivity was displayed between N- resulted in recovered starting materials 22 and 23, whilst
Boc- and N-Cbz-protected amino acids in the Passerini re- more drastic conditions [hydrogenation at 4.1 bar of H2, in
action (entries 1 and 3, Table 1) but lower yields were ob- the presence of Pd/C or Pd(OH)2] generated complex mix-
served using Cbz as protecting group in the second step of tures of degradation byproducts.
the PADAM sequence for the generation of products 15
and 16. Gratifyingly, N-Boc-protected amino acids gave
good results affording the desired products 17–21 in high
We then focused on the cleavage of the Boc protecting
group on compound 24. Surprisingly, treatment with TFA
in CH2Cl2, not only resulted in Boc deprotection and
yield. As expected, the intrinsically low stereoselectivity
spontaneous cyclisation, but also in a spontaneous aroma-
of the Passerini reaction11 resulted in products 15–21, to
be isolated as mixtures of diastereoisomers in a ratio rang-
ing from 7:3 to 1:1.
Table 2 Oxidation of a-Hydroxy Amides 17–25a
R3
NHPG
R3
NHPG
To exemplify the utility of compounds 15–21 as interest-
ing intermediates for the synthesis of heterocyclic scaf-
folds as outlined in Scheme 2, we decided to oxidise the
free secondary alcohol present on these compounds and
use the resulting a-keto amide for the formation of dihy-
dropyrazinones of general formula 4. Oxidation with IBX
in DMSO proceeded smoothly affording the desired prod-
ucts 22–28 in good yield (Table 2). Again, substrates con-
taining a Boc-protected amine functionality proved to be
superior to their Cbz-protected equivalents. Products de-
riving from optically pure amino aldehydes were obtained
as single diastereoisomers at this stage, confirming that no
racemisation/epimerisation occurred during the two steps
of the PADAM sequence. Nevertheless, it was observed
that products 22–28 tend to epimerise if stored for some
days at room temperature, presumably due to the acidity
of the proton in the a-position to the keto amide function-
ality.
IBX, DMSO
r.t.
R1
N
R1
N
O
O
O
O
R2
NHR4
R2
NHR4
OH
O
15–21
22–28
Entry
15–21
15
Yield of 22–28 (%)
22 79
1
2
3
4
5
6
7
16
23 68
17
24 93
18
25 83
19
26 81
20
27 73
21
28 83
To complete our synthetic plan we needed to cleave the
protecting group still present on products 22–28 in order
to promote the intramolecular formation of dihydropy-
a Reaction conditions: a-hydroxy amide (1.0 equiv) and IBX (1.5
equiv) in DMSO for 3–16 h at r.t.
Synlett 2011, No. 14, 2009–2012 © Thieme Stuttgart · New York

LETTER
Synthesis of Polyfunctionalised 2(1H)-Pyrazinones
2011
tisation to give the final compound 29, which was ob- oxidised to pyrazinone upon exposure to air, compound
tained in good yield with no trace of the corresponding 33 was subjected to the same conditions described in
dihydropyrazinone (Scheme 4). In an attempt to survey Scheme 4, and it was readily converted into 30
the generality of this reaction, we reacted 25 and 27 under (Scheme 5).
the same acidic conditions, and 2(1H)-pyrazinones 30 and
31 were again afforded in high yield. Intrigued by this un-
expected aromatisation, we attempted to directly convert
the PADAM adducts into the final 2(1H)-pyrazinones via
a one-pot procedure. Therefore, compound 21 was sub-
jected to a microwave-assisted oxidation employing IBX
in EtOAc; the reaction proceeded smoothly in 10 minutes
at 100 °C.
Even though we were initially more interested in the prep-
aration of dihydropyrazinones, we were pleased to find a
novel route to access highly functionalised 2(1H)-pyrazi-
nones, as they are important heterocyclic constituents of
natural products such as dragmacidin D, E, and F,13
ma’edamine A and B14 and flavacol. Moreover, they have
been applied as building blocks in organic synthesis,15 and
they are important heterocyclic scaffolds that can be
found in a wide variety of compounds exhibiting impor-
tant biological activity.16
R
O
NHBoc
O
R
O
N
50% TFA in CH2Cl2
r.t.
NH
O
NHn-Bu
NHBoc
O
1) HCl (concd), EtOAc
2) K2CO3
Bn
NHn-Bu
N
H
Bn
N
O
NH
O
NHn-Bu
O
24, R = i-Pr
25, R = CH3
29, R = i-Pr, 81%
30, R = CH3, 79%
Bn
NHn-Bu
O
N
H
Bn
O
25
33, 63%, dr 85:15
20% TFA in
CH2Cl2, r.t.
BocHN
O
N
O
50% TFA in CH2Cl2
r.t.
N
O
NHn-Bu
O
30, 99%
O
N
Scheme 5 Formation of dihydropyrazinone 33 using HCl
NHn-Bu
27
31, 82%
In summary we have expanded the scope of the PADAM
methodology using orthogonally protected a-amino acids
and demonstrated the utility of this strategy to the novel
synthesis of interesting heterocycles with three points of
diversity. Present studies are focussing on better under-
standing the effect of TFA on the aromatisation step. The
combinatorial application of our novel one-pot procedure
for the straightforward assembly of 2(1H)-pyrazinones is
also being examined. It is worth noting that, being the fi-
nal products achiral, also less common a-amino acids and
a-amino aldehydes can be used as inputs without the need
to preparing them in optically pure forms.
BocHN
N
O
IBX (1.2 equiv)
EtOAc, MW 100 °C, 10 min
then TFA, MW 100 °C, 5 min
N
N
NHt-Bu
O
OH
O
O
NHt-Bu
21
32, 70%
Scheme 4 Synthesis of 2(1H)-pyrazinones 29–32
Upon oxidation, IBX side products, insoluble in EtOAc at
room temperature, were filtered off; subsequent TFA ad-
dition and further heating (5 min at 100 °C) afforded
pyrazinone 32 in an overall 70% yield after column chro-
matography (Scheme 4), paralleling the results obtained
in two separate synthetic steps.
Representative Procedure for the Oxidation of Intermediates
15–21
Synthesis of (3S)-N-Butyl-3-{[(2S)-2-(N-Boc-amino)propio-
nyl]amino}-4-phenyl-2-oxybutanamide (25)
Attempts to avoid aromatisation performing the reaction
in the presence of NaBH(OAc)3 or under a hydrogen at-
mosphere in the presence of Pd catalysts were fruitless.
Interestingly, the desired dihydropyrazinone was obtained
by using different conditions for the cleavage of the Boc
group according to a protocol reported by Najera et al.12
In this case, when 25 was treated with concentrated HCl
in place of TFA, product 33 was obtained in high yield, al-
though as an 85:15 mixture of epimers, presumably due to
the configurational instability of the position a to the keto
amide functionality under the reaction conditions. To con-
firm that TFA caused the unexpected aromatisation, pre-
sumably via formation of transient species immediately
Substrate 18 (51 mg, 0.12 mmol) was added to a solution of IBX (51
mg, 0.18 mmol) in DMSO (1.5 mL). The resulting mixture was vig-
orously stirred for 4 h and the mixture freeze-dried. The resulting
white solid was purified by flash chromatography (SiO2, PE–EtOAc
= 8:2 to 1:1) to give 25 (43 mg, 83%) as a white solid (mp 144.1–
145.7 °C). Rf = 0.49 (PE–EtOAc = 1:1). 1H NMR (300 MHz,
CDCl3): d = 7.34–7.16 (3 H, m), 7.13–7.05 (2 H, m), 6.92 (1 H, t,
J = 6 Hz), 6.73 (1 H, br d, J = 14 Hz), 5.54 (1 H, dt, J = 14, 7 Hz),
4.94 (1 H, br s), 4.13 (1 H, m), 3.40–3.29 (3 H, m), 3.14 (1 H, dd,
J = 14, 7 Hz), 1.65–1.48 (2 H, m), 1.43 (9 H, s), 1.42–1.32 (2 H, m),
1.29 (3 H, t, J = 7 Hz), 0.95 (3 H, t, J = 7 Hz). 13C NMR (75 MHz,
CDCl3): d = 195.4, 172.2, 159.0, 154.3, 135.6, 129.4, 128.6, 127.1,
80.1, 55.6, 49.9, 39.1, 37.2, 31.2, 28.3, 20.0, 18.2, 13.6; HRMS
(ES+): m/z calcd for C22H33N3O5Na [M + Na]+: 442.2312; found:
442.2326.
Synlett 2011, No. 14, 2009–2012 © Thieme Stuttgart · New York

2012
A. Basso et al.
LETTER
Representative Procedure for the Synthesis of Products 29–31
Synthesis of 3-Benzyl-N-butyl-6-methyl-5-oxo-4,5-dihydropy-
razine-2-carboxamide (30)
(8) De Moliner, F.; Crosignani, S.; Banfi, L.; Riva, R.; Basso, A.
J. Comb. Chem. 2010, 12, 613.
(9) We have already applied this concept using the same PG for
the a-amino aldehyde and the a-amino acid (ref. 6a).
(10) (a) For the synthesis of 7a–c, see: Wen, J. J.; Crews, C. M.
Tetrahedron: Asymmetry 1998, 7, 1855. (b) The absence
of racemisation was checked by NMR analysis of the
corresponding Mosher esters obtained by aldehyde
reduction with NaBH4 and subsequent reaction with (R)-
Mosher’s chloride. We found that when the reduction with
LiAlH4 was performed in THF partial racemisation (5–10%)
occurred, whilst complete retention of configuration was
observed in Et2O.
Substrate 25 (42 mg, 0.095 mmol) was dissolved in a TFA–CH2Cl2
mixture (2 mL, 1:1) and stirred at r.t. for 1 h. After this time the
crude mixture was concentrated in vacuo and purified by flash chro-
matography (SiO2, CH2Cl2–MeOH = 98:2) to give 30 (24 mg, 79%)
as a white solid (mp 171.1–173.0 °C); Rf = 0.53 (CH2Cl2–MeOH =
9:1). 1H NMR (300 MHz, CDCl3): d = 7.86 (1 H, t, J = 6 Hz), 7.40–
7.20 (5 H, m), 4.66 (2 H, s), 3.50–3.38 (2 H, m), 2.41 (3 H, s), 1.66–
1.52 (2 H, m), 1.49–1.35 (2 H, m), 0.96 (3 H, t, J = 7 Hz). 13C NMR
(75 MHz, CDCl3): d = 164.0, 157.7, 152.9, 141.5, 136.5, 129.5,
128.2, 127.2, 123.0, 39.0, 35.5, 31.8, 20.2, 19.8, 13.8. MS (EI): m/z
(%) = 299 (63) [M+], 226 (100), 198 (75), 129 (31), 91 (21), 72 (52),
42 (12). HRMS (ES+): m/z calcd for C17H21N3O2Na [M + Na]+:
322.1526; found: 322.1516.
(11) Banfi, L.; Riva, R. In Organic Reactions; Overman, L. E.,
Ed.; Wiley-VCH: Weinheim, 2005, 1.
(12) (a) Abellan, T.; Chinchilla, R.; Galindo, N.; Guillena, G.;
Najera, C.; Sansano, J. M. Eur. J. Org. Chem. 2000, 2689.
(b) Najera, C.; Abellan, T.; Sansano, J. M. Eur. J. Org.
Chem. 2000, 2809. (c) Abellan, T.; Mancheno, B.; Najera,
C.; Sansano, J. M. Tetrahedron 2001, 57, 6627.
Microwave-Assisted One-Pot Synthesis of N-(tert-Butyl)-3-iso-
propyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrazine-1-
carboxamide (32)
Substrate 21 (70 mg, 0.17 mmol) was dissolved in EtOAc (1 mL),
IBX (56 mg, 0.20 mmol) was added, and the resulting suspension
heated in a MW oven at 100 °C (150 W) for 10 min. After this time
TLC analysis showed complete conversion, thus the crude mixture
was filtered, washed with EtOAc (1 mL), and TFA (1 mL) was add-
ed to the filtrate. The resulting solution was then heated in a MW
oven at 100 °C (50 W) for 5 min. Solvents were then evaporated and
the crude purified by flash chromatography (SiO2, EtOAc–PE =
6:4) to give 32 (35 mg, 70% over two steps) as a white foam; Rf =
(13) (a) Wright, A. E.; Pomponi, S. S.; Cross, S. S.; McCarthy, P.
J. Org. Chem. 1992, 57, 4772. (b) Capon, R. J.; Rooney, F.;
Murray, L. M.; Collins, E.; Sim, A. T. R.; Rostas, J. A. P.;
Butler, M. S.; Carroll, A. R. J. Nat. Prod. 1998, 61, 660.
(c) Wright, A. E.; Pomponi, S. A.; Jacobs, R. S. WO
9942092, 1999; Chem. Abstr. 1999, 131, 175081.
(d) Cutignano, A.; Bifulco, G.; Bruno, I.; Casapullo, A.;
Gomez-Paloma, L.; Riccio, R. Tetrahedron 2000, 56, 3743.
(14) Hirano, K.; Kubota, T.; Tsuda, M.; Watanabe, K.; Fromontc,
J.; Kobayashi, J. Tetrahedron 2000, 56, 8107.
1
0.37 (EtOAc–PE = 6:4). H NMR (300 MHz, CDCl3): d = 7.97 (1
H, s), 3.99 (2 H, t, J = 7 Hz), 3.55 (2 H, t, J = 7 Hz), 3.41 (1 H, hept,
J = 7 Hz), 1.94 (2 H, m), 1.80 (2 H, m), 1.44 (9 H, s), 1.23 (6 H, t,
J = 7 Hz). 13C NMR (75 MHz, CDCl3): d = 164.7, 156.5, 156.0,
142.7, 122.3, 50.7, 42.9, 30.5, 29.0, 25.3, 21.5, 20.2, 18.1. MS (EI):
m/z (%) = 291 (20) [M+], 235 (15), 218 (100), 83 (18), 41 (6).
HRMS (ES+): m/z calcd for C16H25N3O2Na [M + Na]+: 314.1839;
found: 314.1831.
(15) (a) Loosen, P. K.; Tutonda, M. G.; Khorasani, M. F.;
Compernolle, F.; Hoornaert, G. J. Tetrahedron 1991, 47,
9259. (b) Loosen, P. K.; Khorasani, M. F.; Toppet, S. M.;
Hoornaert, S. M. Tetrahedron 1991, 47, 9269.
(c) Rombouts, F. J. R.; De Borggraeve, W.; Toppet, S. M.;
Compernolle, F.; Hoornaert, G. J. Tetrahedron Lett. 2001,
42, 7397. (d) Pawar, V. G.; De Borggraeve, W. M. Synthesis
2006, 2799. (e) Singh, B. K.; Appukkuttan, P.; Claerhout,
S.; Parmar, V. S.; Van der Eycken, E. Org. Lett. 2006, 8,
1863. (f) Garella, D.; Tagliapietra, S.; Mehta, V. P.;
Van der Eycken, E.; Cravotto, G. Synthesis 2010, 136.
(16) For selected examples of bioactive compounds containing
the 2(1H)-pyrazinone moiety, see: (a) Janssen, P. A. J.;
Van Aken, K. J. A.; Lewi, P. J.; Koymans, L. M. H.;
De Jonge, M. R.; Heeres, J.; Daeyaert, F. F. D.; Hoornaert,
G. J. C.; Compernolle, F. J. C.; Kilonda, A. WO 02078708,
2002; Chem. Abstr. 2002, 137, 294978. (b) Jinsmaa, Y.;
Miyazaki, A.; Fujita, Y.; Li, T.; Fujisawa, Y.; Shiotani, K.;
Tsuda, Y.; Yokoi, T.; Ambo, A.; Sasaki, Y.; Bryant, S. D.;
Lazarus, L. H.; Okada, Y. J. Med. Chem. 2004, 47, 2599.
(c) Heeres, J.; de Jonge, M. R.; Koymans, L. M. H.;
Daeyaert, F. F. D.; Vinkers, M.; Van Aken, K. J. A.; Arnold,
E.; Das, K.; Kilonda, A.; Hoornaert, G. J.; Compernolle, F.;
Cegla, M.; Azzam, R. A.; Andries, K.; de Béthune, M.-P.;
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Lindsjoe, M.; Loenn, H.; Lundkvist, M.;
Acknowledgment
PRIN06 and Fondazione S. Paolo are gratefully acknowledged for
financial support.
References and Notes
(1) Present address: P. Tosatti, School of Chemistry, University
of Leeds, Leeds LS2 9JT, UK.
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