A flexible six-component reaction to access constrained depsipeptides based on a dihydropyridinone core

Article abstract of DOI:10.1021/jo701978v

(Chemical Equation Presented) Highly functionalized and conformationally constrained depsipeptides based on a dihydropyridin-2-one core are prepared by the combination of a four- and a three-component reaction. The synthesis combines a one-pot Horner-Wads

Full text of DOI:10.1021/jo701978v

SCHEME 1. MCR Leading to Isonitrile-Functionalized
3,4-DHP-2-ones
A Flexible Six-Component Reaction To Access
Constrained Depsipeptides Based on a
Dihydropyridinone Core
Monica Paravidino, Rachel Scheffelaar, Rob F. Schmitz,
Frans J. J. de Kanter, Marinus B. Groen, Eelco Ruijter, and
Romano V. A. Orru*
Vrije UniVersiteit Amsterdam, Department of Chemistry &
Pharmaceutical Sciences, De Boelelaan 1083,
1081 HV Amsterdam, The Netherlands
reaction sequences, in which a common intermediate is trapped
to create different complex scaffolds in a minimal number of
steps.
orru@few.Vu.nl
Although reports on novel MCRs appear regularly in the
recent literature,3 MCRs using more than five components are
very rare. A landmark in this context is the seven component
reaction (7CR) reported by Do¨mling and Ugi,4 which was
basically a one-pot combination of a modified Asinger-4CR and
Ugi-4CR. In this 7CR, two different aldehydes, NaSH, NH3,
an isocyanide, CO2, and a primary alcohol are combined to
produce thiazolidines efficiently. However, NaSH, NH3, and
CO2 are invariable components in this reaction.
ReceiVed September 8, 2007
Recently, we have reported several new MCRs based on a
modular sequence.5 The common factor in these reactions is
the application of 1-azadiene intermediate 4, generated in situ
by reaction of phosphonates 1, nitriles 2, and aldehydes 3 via
a Horner-Wadsworth-Emmons (HWE) reaction (Scheme 1).6
The azadiene intermediate can be trapped by isocyanates or
isothiocyanates to afford functionalized 3,4-dihydropyrimidine-
2-ones,5 2-aminothiazines,5b and dihydropyrimidine-2-thiones.5b
In an elaboration of this chemistry, we examined the application
of R-aryl isocyanoacetates 5 as the fourth, cyclizing, component
to trap 1-azadiene 4 (Scheme 1).7 The resulting 3,4-dihydro-
pyridin-2-ones 6 (3,4-DHP-2-ones) were obtained in good to
excellent yields and with full diastereoselectivity in favor of
the cis isomer.
The 4CR could be performed with aliphatic and aromatic
nitriles and aromatic and R,â-unsaturated aldehydes affording
a small library of isonitrile-functionalized 3,4-DHP-2-ones 6.
For convenience, a selection of examples (6a-g) are also
included in Table 1. We only employed isocyanides 5 with an
aromatic R3-group, because in these cases the 4CR proceeds in
a highly diastereoselective fashion.7
Highly functionalized and conformationally constrained
depsipeptides based on a dihydropyridin-2-one core are
prepared by the combination of a four- and a three-
component reaction. The synthesis combines a one-pot
Horner-Wadsworth-Emmons/cyclocondensation sequence
leading to isonitrile-functionalized DHP-2-ones with an
isonitrile-based Passerini multicomponent reaction (MCR).
Substituents could be independently varied at six different
positions. The two MCRs could also be performed as a one-
pot procedure, simplifying the protocol and leading to a new
and highly variable six-component process.
One of the main challenges in synthetic organic chemistry is
the rapid and efficient construction of collections of structurally
complex and diverse small molecules. This can be most
efficiently achieved by performing multiple reaction steps in a
single operation. The development of such processes in which
several bonds are formed without isolation of intermediates
receives considerable attention.1 An important class of these
reactions is constituted by multicomponent reactions (MCRs),2
which are particularly valued because they combine readily
available building blocks with a range of functionalities in a
single transformation. MCRs form the perfect basis for modular
We envisioned the ability of isonitrile-functionalized 3,4-
DHP-2-ones 6 to react as isocyanide components in a subsequent
(3) For example, see: (a) Sun, X.; Janvier, P.; Zhao, G.; Bienayme´, H.;
Zhu, J. Org. Lett. 2001, 3, 877 -880. (b) Lie´by-Muller, F.; Constantieux,
T.; Rodriguez, J. J. Am. Chem. Soc. 2005, 127, 17176-17177. (c) El Ka¨ım,
L.; Grimaud, L.; Oble, J. Angew. Chem. 2005, 117, 8175-8178; Angew.
Chem., Int Ed. 2005, 44, 7961-7964. (d) Elders, N.; Schmitz, R. F.; de
Kanter, F. J. J.; Ruijter, E.; Groen, M. B.; Orru, R. V. A. J. Org. Chem.
2007, 72, 6135-6142.
(4) Do¨mling, A.; Ugi, I. Angew. Chem. 1993, 105, 634-635; Angew.
Chem., Int. Ed. 1993, 32, 563-564.
(5) (a) Vugts, D. J.; Jansen, H.; Schmitz, R. F.; De Kanter, F. J. J.; Orru,
R. V. A. Chem. Commun. 2003 2594-2595. (b) Vugts, D. J.; Koningstein,
M. M.; Schmitz, R. F.; De Kanter, F. J. J.; Groen, M. B.; Orru, R. V. A.
Chem. Eur. J. 2006, 12, 7178-7179.
(1) For an excellent book, see: Tietze, L. F.; Brasche, G.; Gericke, K.
M. Domino Reactions in Organic Synthesis; Wiley-VCH: Weinheim, 2006.
(2) (a) Orru, R. V. A.; de Greef, M. Synthesis 2003, 1471-1499. (b)
Do¨mling, A. Chem. ReV. 2006, 106, 17-89. (c) Do¨mling, A.; Ugi, I. Angew.
Chem. 2000, 112, 3300-3344; Angew. Chem., Int. Ed. 2000, 39, 3168-
3210. (d) Zhu, J. Eur. J. Org. Chem. 2003, 1133-1144. (e) Zhu, J.;
Bienayme, H. Multicomponent Reactions; Wiley-VCH: Weinheim, 2006.
(6) (a) Shin, W. S.; Lee, K.; Oh, D. Y. Tetrahedron Lett. 1995, 36, 281-
282. (b) Lee, K.; Oh, D. Y. Synthesis 1991, 213-214.
(7) Paravidino, M.; Bon, R. S.; Scheffelaar, R.; Vugts, D. J.; Znabet,
A.; Schmitz, R. F.; De Kanter, F. J. J.; Lutz, M.; Spek, A. L.; Groen, M.
B.; Orru, R. V. A. Org. Lett. 2006, 8, 5369-5372.
10.1021/jo701978v CCC: $37.00 © 2007 American Chemical Society
Published on Web 11/13/2007
J. Org. Chem. 2007, 72, 10239-10242
10239

TABLE 1. Passerini Follow-up Chemistry Using Several DHP-2-ones 6 To Afford the Corresponding Depsipeptides 7a
a Unless otherwise noted (see the Supporting Information), the Passerini-3CRs were carried out using 0.7 M of DHP-2-one 6 and 1.1 equiv of both
aldehyde/ketone and acid. Full conversion to 7 was reached after stirring for 1-6 days at room temperature in CH2Cl2, after which the Passerini products
7 were isolated as a 1:1 mixture of diastereomers. b Isolated yields are reported. c A large excess of paraformaldehyde (6 equiv) was used. d 7g was obtained
as a 1:1:1:1 mixture of four diastereomers. e Along with the product, 34% of side product 8 was also isolated. PMP ) p-methoxyphenyl, PCP ) p-chlorophenyl.
SCHEME 2. Formation of Side Product 8
The modular setup of our approach allows for optimal
flexibility with respect to the diversity points, and independent
variation of all of the components involved in both MCRs, with
the exception of 1, should be possible. Furthermore, the
generally mild reaction conditions for both the HWE/cyclocon-
densation-4CR as well as for the Passerini-3CR led us to study
the one-pot combination of both reactions to give a novel 6CR,
thus simplifying the procedure and offering unprecendented
opportunities for complexity generation and diversification. In
this paper, we wish to report the results of our study.
3,4-DHP-2-ones 6a-g were reacted with a range of com-
mercially available aldehydes and acids under standard Passerini
conditions (CH2Cl2, rt). The expected depsipeptides 7a-o
were successfully obtained in reasonable to excellent yield.
Table 1 shows the broad substrate scope of this reaction typical
for Passerini reactions. Due to the absence of stereo-
chemical induction that is intrinsic to the Passerini reaction, a
1:1 mixture of inseparable diastereomers was obtained.10
No limitations were found in the aldehyde component since
aliphatic, aromatic, and heteroaromatic aldehydes could be
used. The use of ketones as the carbonyl component was also
allowed, albeit with a slight decrease in yield (Table 1, entry
13). Furthermore, several acids (including an N-protected
amino acid, entry 7) were successfully applied and afforded
the corresponding products 7 in good to excellent yield.
Moreover, no restriction was found with respect to the DHP-
2-one input in the efficiency of the Passerini reaction. The low
Passerini-3CR reaction.8 In this way, conformationally con-
strained depsipeptides based on the DHP-2-one core should be
accessible in only two steps. Depsipeptides, and cyclodepsipep-
tides in particular, represent an important class of natural
products displaying diverse biological activities.9 The 3,4-DHP-
2-ones like 6 have great potential in the construction of
Freidinger-type â-turn mimics.9a Conformationally constrained
depsipeptides based on the 3,4-DHP-2-one core such as those
resulting from the current multicomponent approach are there-
fore promising candidates for lead discovery.
(8) Banfi, L.; Riva, R. Org. React. 2005, 65, 1-140.
(9) (a) Sarabia, F.; Chammaa, S.; Ruiz, A. S.; Ortiz, L. M.; Herrera, F.
J. L. Curr. Med. Chem. 2004, 11, 1309-1332. (b) Freidinger, R. M.; Veber,
D. F.; Perlow, D. S.; Brooke, J. R.; Saperstein, R. Science 1980, 210, 656-
658.
(10) For exceptions, see: (a) Cuny, G.; Ga´mez-Montan˜o, R.; Zhu, J.
Tetrahedron 2004, 60, 4879-4885. (b) Krishna, P. R.; Dayaker, G.;
Reddy, P. V. N. Tetrahedron Lett. 2006, 47, 5977-5980. (c) Frey, R.;
Galbraith, S. G.; Guelfi, S.; Lamberth, C.; Zeller, M. Synlett 2003, 1536-
1538.
10240 J. Org. Chem., Vol. 72, No. 26, 2007

TABLE 2. One-Pot DHP-2-one-Passerini Reaction To Produce Depsipeptides 7a
a In general, the reactions were carried out using 0.2 M of 1, 1.1 equiv of n-BuLi, and 1 equiv of 2, 3, and 5. After formation of 6 was complete (TLC),
the mixture was concentrated to 0.6-0.7 M, and 1.1 equiv of aldehyde and acid were added. Depsipeptides 7 were usually obtained by allowing the reactions
to stir for an additional 7-9 days at rt. For more details, see the Supporting Information. b Isolated yields are reported. c The whole sequence was performed
at 0.2 M concentration for 7 days at rt. PMP ) p-methoxyphenyl, PCP ) p-chlorophenyl.
yield of product 7l is caused by a side reaction leading to
formamide 8, most likely the result of a reaction between the
isonitrile and the acid component followed by an acyl migration
involving the free amide NH in the DHP-2-one (Scheme 2).
No acylated Passerini product was observed, excluding an
intermolecular process. A similar side reaction was observed
in two reports describing the Passerini reaction in aqueous
media; in these cases, the primary reaction was followed by
hydrolysis rather than acyl migration.11 This side reaction occurs
primarily upon dilution, which was required for this specific
Passerini reaction (0.25 M instead of 0.7 M) for solubility
reasons.
Thus, diethyl methylphosphonate, isobutyronitrile, p-meth-
oxybenzaldehyde, and methyl 2-isocyano-2-phenylacetate were
combined to form the corresponding 3,4-DHP-2-one 6a. The
concentration for this HWE/cyclocondensation-4CR was kept
similar (0.2 M) compared to that of the reaction used in the
two-step sequence (see entry 1, Table 1). After the in situ
formation of 6a was complete, the solution was concentrated
to 0.6-0.7 M (similar to the Passerini conditions described in
Table 1) and isobutyraldehyde and propionic acid were added.
The one-pot six-component procedure performed surprisingly
well and after the reaction was complete, we could isolate
depsipeptide 7a in 40% yield. In fact, this yield was the same
as the overall yield obtained via the two-step procedure (41%,
see entry 1, Table 1).
The initial conditions proved more generally applicable and,
in addition to 7a, the conformationally constrained depsipeptides
7c, 7h, and 7j were formed smoothly (see Table 2). Actually,
the reaction performs very well in one pot considering the
complexity of the reaction system, and all the isolated yields
are comparable with the combined yields of the two separate
MCRs, indicating that no additional side reactions occur. It
should be noted, however, that in the one-pot procedure the
Passerini reaction proceeded relatively slow, with reaction times
up to 10 days, probably due to the use of THF instead of
CH2Cl2 as a solvent.14 Performing the whole sequence at 0.2
M concentration leads to comparable reaction rates and overall
yield of the depsipeptide with respect to the same reaction in
which the Passerini reaction is performed at 0.6-0.7 M
concentration (compare entries 4 and 5, Table 2). This result
makes the tandem DHP-2-one/Passerini reaction in fact a true
one-pot 6CR.
The reported Passerini reactions generally reached full
conversion in 1-6 days, with some exceptions.12 Such reaction
rates are quite typical for the Passerini reaction.13
To accelerate the reaction, an additional 1 equiv of aldehyde
and acid was added in some cases.12 Furthermore, it is known
that the use of water as a cosolvent can accelerate the Passerini
reaction.11,13 However, performing the reaction of entry 2 (Table
1) in H2O or THF/H2O mixtures instead of CH2Cl2 did not result
in significant rate enhancement of the reaction. With this rather
flexible two-step procedure for constrained depsipeptides in
hand, we now turned to study the combination of both MCRs
in one pot resulting in a six-component reaction. The rather
mild reaction conditions under which both the HWE/cyclocon-
densation-4CR and the Passerini-3CR operate suggested that
only slight modifications of the original conditions would be
required. For the HWE/cyclocondensation-4CR, we decided to
apply stoichiometric amounts of all components except for the
slight excess of n-BuLi (1.1 equiv). In addition, THF was used
as the solvent in the whole sequence, which is a slight
modification for the Passerini-3CR. Under these conditions, the
one-pot synthesis of depsipeptide 7a was first investigated (Table
2, entry 1).
In conclusion, we showed that the retained isocyanide
functionality in 3,4-DHP-2-ones 6 synthesized via a HWE/
cyclocondensation-4CR allows subsequent isonitrile-based mul-
ticomponent follow-up chemistry. The isocyano group proved
indeed an excellent synthetic handle for additional MCRs. A
follow-up Passerini-3CR reaction led to a series of complex
DHP-2-one based conformationally constrained depsipeptides
(11) (a) Mironov, M. A.; Ivantsova, M. N.; Tokareva, M. I.; Mokrushin,
V. S. Tetrahedron Lett. 2005, 46, 3957-3960. (b) Extance, A. R.;
Benzies, D. W. M.; Morrish, J. J. QSAR Comb. Sci. 2006, 25, 484-
490.
(12) For details, see the Supporting Information.
(13) (a) Pirrung, M. C.; Das Sarma, K. Tetrahedron 2005, 61, 11456-
11472. (b) Pirrung, M. C.; Das Sarma, K. J. Am. Chem. Soc. 2004, 126,
444-445.
(14) When the solvent is changed from THF to CH2Cl2 after formation
of the DHP-2-one, the reaction rate of the Passerini reaction can be increased
substantially.
J. Org. Chem, Vol. 72, No. 26, 2007 10241

5.01 (d, J ) 6.7 Hz, 1H), 4.90 (d, J ) 4.3 Hz, 1H), 4.74 (d, J )
4.3 Hz, 1H), 3.78 (s, 3H), 3.76 (s, 3H), 2.42 (q, J ) 7.5 Hz, 2H),
2.21-1.87 (m, 4H + 2H), 1.20 (t, J ) 7.6 Hz, 3H), 0.98 (t, J )
7.6 Hz, 3H), 0.94-0.87 (m, 6H + 6H), 0.72 (d, J ) 6.9 Hz, 6H),
0.69 (d, J ) 6.8 Hz, 3H), 0.48 (d, J ) 6.8 Hz, 3H); 13C NMR (63
MHz, CDCl3) δ (ppm) 173.4 (C), 172.5 (C), 171.5 (C), 171.4 (C),
168.5 (C), 168.1 (C), 159.4 (2 × C), 141.0 (C), 140.3 (C), 138.9
(C), 138.8 (C), 130.9 (C), 130.2 (CH), 129.8 (C), 129.7 (CH), 128.5
(CH), 128.3 (CH), 128.1 (CH), 128.0 (CH), 127.8 (CH), 127.5 (CH),
114.4 (2 × CH), 105.6 (CH), 105.0 (CH), 78.3 (CH), 77.4 (CH),
64.1 (C), 63.7 (C), 55.7 (CH3), 55.6 (CH3), 42.4 (CH), 41.4 (CH),
31.6 (2 × CH), 30.9 (CH), 30.5 (CH), 28.0 (CH2), 27.7 (CH2),
20.5 (CH3), 20.1 (CH3), 20.0 (CH3), 19.3 (CH3), 18.9 (CH3), 17.0
(CH3), 16.8 (CH3), 9.6 (CH3), 9.3 (CH3); IR (NaCl) 2966 (s), 1749
(s), 1668 (s), 1510 (s), 1178 (s); HRMS (EI, 70 eV) calcd for
C29H36N2O5 (M+) 492.2624, found 492.2624; MS (EI, 70 eV) m/z
320 (28), 319 (100), 318 (46), 215 (10), 172 (12), 104 (9), 57 (14).
Passerini Product 7c. General Procedure I. Reaction between
6c, isobutyraldehyde, and propionic acid afforded after 1 day 7c
(40 mg, 73%) as a 1:1 mixture of two diastereoisomers. Column
chromatography was performed with c-hexane/EtOAc 7:3. General
Procedure II. Compound 7c (190 mg) was obtained in 36% overall
yield from phosphonate 1 after stirring for 8 days: 1H NMR (250
MHz, CDCl3) δ (ppm) 7.74-7.18 (m, 16H + 16H), 5.88 (d, J )
6.9 Hz, 1H), 5.85 (d, J ) 7.0 Hz, 1H), 5.31 (d, J ) 6.7 Hz, 1H),
5.27 (d, J ) 6.8 Hz, 1H), 4.86 (d, J ) 4.6 Hz, 1H), 4.72 (d, J )
4.4 Hz, 1H), 2.44 (q, J ) 7.8 Hz, 2H), 2.23-1.91 (m, 3H + 1H),
1.20 (t, J ) 7.6 Hz, 3H), 1.00 (t, J ) 9.4 Hz, 3H), 0.74-0.68 (m,
6H + 3H), 0.52 (d, J ) 6.8 Hz, 3H); 13C NMR (101 MHz, CDCl3)
δ (ppm) 173.5 (C), 172.7 (C), 170.7 (C), 168.8 (C), 168.4 (C),
138.4 (C), 138.3 (C), 136.8 (C), 136.1 (C), 136.0 (C), 135.4 (C),
134.2 (2 × C), 134.0 (C), 133.9 (C), 130.7 (CH), 130.2 (CH), 129.7
(2 × CH), 129.4 (CH), 129.3 (CH), 129.2 (CH), 128.9 (CH), 128.7
(CH), 128.6 (CH), 128.5 (CH), 128.3 (CH), 127.5 (CH), 127.3 (CH),
125.4 (CH), 108.0 (CH), 107.7 (CH), 78.1 (CH), 77.5 (CH), 63.8
(C), 63.5 (C), 43.4 (CH), 42.2 (CH), 30.9 (CH), 30.5 (CH), 27.9
(CH2), 27.7 (CH2), 19.3 (CH3), 18.8 (CH3), 17.2 (CH3), 16.8 (CH3),
9.6 (CH3), 9.3 (CH3); IR (NaCl) 2352 (m), 2343 (m), 1733 (s),
1717 (s), 1652 (s), 1635 (s), 739 (s); HRMS (EI, 70 eV) calcd for
C31H31ClN2O4 (M+) 530.1972, found 530.1967; MS (EI, 70 eV)
m/z 359 (38), 358 (37), 357 (100), 244 (33), 242 (99), 215 (17), 71
(27), 57 (42).
7. The combination of our MCR and the Passerini reaction in
one pot was also demonstrated, affording a novel one-pot 6CR.
The yields of the one-pot, six-component process were com-
parable to those of the two-step procedure. All of the six
components in the novel 6CR can be varied, opening the way
to efficient generation of arrays of DHP-2-one-functionalized
depsipeptidic scaffolds from simple, commercially available
starting materials. These results demonstrate the strength of the
concept of unification of MCRs.
Experimental Section
General Procedure I for the Passerini Reaction. The reactions
were generally carried out at a concentration of 0.70 M of DHP-
one and 0.77 M of the other two components in CH2Cl2. Deviations
from these concentrations are due to solubility problems and are
reported for every product. The dihydropyridone was dissolved in
DCM, followed by addition of 1.1 equiv of carbonyl compound
and 1.1 equiv of carboxylic acid. After being stirred at rt until
completion, the reaction mixture was concentrated in vacuo and
the crude product purified by column chromatography. The resulting
diastereomeric mixture could not be separated in any case and the
1
diastereomeric ratio was determined via H NMR analysis for all
the products with the exception of 7g (HPLC).
General Procedure II for the One-Pot DHP-one-Passerini
MCR. The synthesis was always carried out at a concentration of
0.20 M of phosphonate 1, 0.22 M of n-BuLi, 0.20 M of nitrile 2,
aldehyde 3, and isocyanoacetate 5 in dry THF. Always 1.0 mmol
of the limiting reagent, the phosphonate, was used. 1.1 Equiv. of
n-BuLi (1.6 M solution in hexanes) were added at -78 °C to a
stirred solution of phosphonate in THF. After the mixture was stirred
at -78 °C for 1.5 h, the nitrile (1.0 equiv) was added, and the
mixture was then stirred at -78 °C for 45 min, at -40 °C for 1 h,
and at -5 °C for 30 min. The aldehyde (1.0 equiv) was added, and
after being stirred at -5 °C for 30 min, the mixture was allowed
to warm to rt and stirred for 1.5 h. Finally, the isocyanoacetate
(1.0 equiv) was added, and the mixture was stirred overnight at rt
and then concentrated in vacuo up to a concentration of phosphonate
of 0.6-0.7 M. After addition of 1.1 equiv of carbonyl compound
and of acid, the mixture was stirred at rt until completion. The
mixture was concentrated, and the crude product was purified by
chromatography.
Passerini Product 7a. General Procedure I. Reaction between
6a, isobutyraldehyde, and propionic acid afforded after 2 days 7a
(104 mg, 72%) as a 1:1 mixture of diastereoisomers. A concentra-
tion of 0.59 M of 6a was used. Column chromatography was
performed with c-hexane/EtOAc 9:1 f 85:15. General Procedure
II. Compound 7a (201 mg) was obtained in 40% overall yield from
Acknowledgment. We thank Dr. Marek Smoluch (VU-
Amsterdam) for conducting (HR)MS measurements. This work
was financially supported by NWO-VICI.
Supporting Information Available: Full experimental proce-
dures and characterization data for all new compounds. This
materialisavailablefreeofchargeviatheInternetathttp://pubs.acs.org.
1
phosphonate 1 after stirring for 8 days: H NMR (400 MHz, CDCl3)
δ (ppm) 7.71-7.26 (m, 7H + 7H), 7.18 (d, J ) 8.7 Hz, 2H), 7.11
(d, J ) 8.7 Hz, 2H), 6.76 (d, J ) 8.6 Hz, 2H + 2H), 5.36 (d, J )
6.6 Hz, 1H), 5.32 (d, J ) 6.7 Hz, 1H), 5.06 (d, J ) 6.7 Hz, 1H),
JO701978V
10242 J. Org. Chem., Vol. 72, No. 26, 2007