A post-Ugi carbonylation/intramolecular amidation approach toward the synthesis of macrolactams

Article abstract of DOI:10.1016/j.tetlet.2005.01.063

An Ugi-deprotection-carbonylation/intramolecular amidation approach toward the synthesis of novel bicyclic and tricyclic macrolactams is described.

Full text of DOI:10.1016/j.tetlet.2005.01.063

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1697–1701
A post-Ugi carbonylation/intramolecular amidation
approach toward the synthesis of macrolactams
Anil Vasudevan* and Mary K. Verzal
Enabling Chemistry Technologies, Global Pharmaceutical Research and Development, Abbott Laboratories,
100 Abbott ParkRoad, Abbott Park, IL 60064, USA
Received 4 October 2004; revised 13 January 2005; accepted 13 January 2005
Available online 1 February 2005
Abstract—An Ugi-deprotection–carbonylation/intramolecular amidation approach toward the synthesis of novel bicyclic and
tricyclic macrolactams is described.
ꢀ 2005 Published by Elsevier Ltd.
One of the most widely used multi-component reactions
(MCRs) is the Ugi reaction,1 and there have been several
examples of its application towards the synthesis of
libraries of compounds suitable for biological screening.2
Despite its tremendous potential, the Ugi reaction is
somewhat limited in that the products obtained are flex-
ible and peptide like. One solution for making the prod-
ucts from an Ugi MCR more Ôdrug-likeÕ is to constrain
the initial product via a post-condensation modification.
Thus, if one or two of the starting materials were to bear
additional functional groups susceptible to reaction with
each other after formation of the Ugi adduct, then cyclic
structures should be produced, and several elegant
examples of this approach have recently been reported.3
In this report, we wish to describe an intramolecular
carbonylation/amidation of a deprotected Ugi MCR
product to provide macrolactams.
tors.6 Approaches toward the synthesis of these rings
have included attempted cyclizations of dipeptides7 or
intramolecular cyclization of an appropriately function-
alized precursor moiety.8 Recently, intramolecular Stau-
dinger ligation,9 ring-closing metathesis (RCM)10 and
intramolecular ring-expansion strategies11 have been re-
ported, which provide access to seven to nine-membered
lactams.
Our approach toward the synthesis of macrolactams is
shown in Schemes 1 and 2, and involves the use of either
a bifunctional amine component or a bifunctional acid
component in the Ugi MCR. Deprotection of the Ugi
products resulting from the use of these inputs
followed by a carbonylation/intramolecular amidation
should afford macrolactams such as 1 and 2 with
multiple points of diversity.
Seven to ten-membered lactams have gained importance
as potential peptidomimetics,4 as well as constituents of
natural products,5 and cell-signaling pathway inhibi-
The Ugi MCR was found to be fairly general in scope as
shown by the representative products (deprotected) in
Table 1. Various carboxylic acids, isocyanides and
Boc
N
N
O
R2
O
I
O
N
R1-NC
1. 4N HCl
2. [CO]
R2
N
I
R1
NH
MeOH
24 hr
NH2
O
N
Boc
H
+
+
O
R2COOH
HN
O
R1
1
Scheme 1. Representative scheme for the Ugi-deprotection–carbonylation/intramolecular amidation using a bifunctional amine.
Keywords: Macrolactams; Intramolecular amidation; Ugi; Molybdenum; Microwave.
*
Corresponding author. Tel.: +1 847 9386594; fax: +1 847 9350310; e-mail: anil.vasudevan@abbott.com
0040-4039/$ - see front matter ꢀ 2005Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.01.063

1698
A. Vasudevan, M. K. Verzal / Tetrahedron Letters 46 (2005) 1697–1701
R1
R3
O
NHBoc
R
R2-NC
R3
I
O
O
O
MeOH
24 hr
N
1. 4N HCl
2. [CO]
R3
NH
R2
H
+
R1 NH2
N
H
N
1R2
+
HN
Boc
COOH
NH
O
O
I
2
Scheme 2. Representative scheme for the Ugi-deprotection–carbonylation/intramolecular amidation using a bifunctional acid.
Table 1. Products obtained from the Ugi MCR (deprotected) and carbonylation/intramolecular amidation (CIA) sequence
Amine
Aldehyde
Isocyanide
Acid
Ugi product (deprotected)
Yielda
CIA product
Yielda,b
O
O
N
HO
O
HN
H
O
N
N
Boc
N
I
NC
I
75
65
O
NH2
O
O
HN
HN
3
12
O
HN
HN
HN
N
O
O
H
O
OH
O
O
N
N
N
Boc
I
I
NC
69
72
66
81
70
72
77
69
33
53
O
O
O
O
NH2
HN
HN
4
13
Cl
O
HO
O
N
O
H2N
H
H
H
H
O
O
O
O
Cl
N
N
I
Boc
I
I
I
NC
N
O
O
O
HN
Cl
HN
5
14
Cl
HO
O
N
O
O
H2N
NC
Cl
N
Boc
N
I
N
O
O
O
HN
Cl
HN
6
15
HN
I
O
N
O
O
NH2
HO
O
O
N
N
NC
O
N
HN
O
O
Boc
O
HN
7
16
O
O
H2N
I
HN
Boc
H2N
HO
O
O
NH
N
I
N
O
O
NC
O
O
O
HN
HN
8
17
Cl
O
N
N
HN
O
O
H
O
HO
O
Cl
N
NC
Br
Br
N
O
85
62
Boc
O
O
O
NH2
O
HN
HN
O
Cl
O
O
9
18

A. Vasudevan, M. K. Verzal / Tetrahedron Letters 46 (2005) 1697–1701
1699
Table 1 (continued)
Amine
Aldehyde
Isocyanide
Acid
Ugi product (deprotected)
Yielda
CIA product
Yielda,b
H2N
Boc
NH
H
O
NC
O
OH
O
O
HN
N
I
N
O
O
I
88
51
O
HN
H2N
HN
19
10
O
H2N
O
O
O
H
O
O
OH
N
N
H
I
NC
80
70
O
O
NH
N
O
HN
Boc
HN
NH2
O
I
11
20
a mixture of diastereomers, where applicable.
b Isolated yields.
amines were utilized and the products purified via
sequential treatment with PS-trisamine12 and MP-
CO3 to afford pure Ugi products in respectable yields
as mixtures of diastereomers, where applicable.
Changing the base from K2CO3 to Cs2CO3 or DBU also
resulted in formation of significant amounts of 21, as did
the use of no base. Further, the use of alternate Pd
sources such as PdCl2 (dppf) resulted in exclusive forma-
tion of 21. Alterman and co-workers have recently re-
ported the synthesis of phthalides and isoindolinones
via the use of DIEA/DMAP/Pd(OAc)2 and PPh3 as an
additive.19 The use of these conditions for the transfor-
mation of interest in this study did not afford improved
formation of 12 compared to 21. To improve the
absorption of the carbon monoxide generated via the
decomposition of Mo[CO]6, n-Bu3N was used as an
additive14 and the reaction heated at 160 ꢁC in diglyme
for 15and 60 min to afford significantly enhanced for-
mation of 12. The PPh3 was found to be nonessential,
and the optimal conditions for the carbonylation/intra-
molecular amidation were to heat the sterically hindered
substrate with a mixture of Mo[CO]6/Pd(OAc)2/n-Bu3N
in diglyme at 160 ꢁC for 1 h in a sealed tube.20 Aryl
bromides were also found to be effective substrates
for the carbonylation/intramolecular amidation (e.g.,
9), though the reaction mixture had to be charged twice
with Mo[CO]6 and Pd(OAc)2 to afford efficient conver-
sion. The use of 3-aminomethyl pyrrolidine as the amine
input afforded constrained nine-membered macrolac-
tam, 16. Further, the use of a tert-butoxycarbonyl-pro-
tected amino acid as the acid input, followed by
deprotection and intramolecular amidation affords
benzo[f][1,4]diazocine-1,4-dione, 20. Depending on the
chirality of the amine inputs used in this study, the
Ugi-products as well as the macrolactams were obtained
as mixtures of diastereomers.
13
Initial literature reports on the intermolecular amidation
of aryl halides using Pd catalysis by Heck and co-
workers,14 were followed by the extension of this method-
ology to intramolecular amidation by Ban and
co-workers.15 Recently, Rh-catalyzed intramolecular
carbonylation using aldehydes as a source of carbon
monoxide has been reported16—however, this approach
is restricted to the use of tosylated amines. Larhed
and co-workers have reported the use of Mo(CO)6
as a source of CO and demonstrated its application to
intermolecular carbonylation and allylic alkylation.17
Under these conditions, sterically hindered amines
afforded poor results and the effect on sterically hindered
halides was not reported.
Deprotection of the Ugi MCR products with 4 N HCl
afforded the desired amine poised for the carbonyl-
ation/intramolecular amidation reaction. Several condi-
tions were attempted to affect the carbonylation/
intramolecular amidation of a model substrate 3, and
some general trends were apparent. The use of a
K2CO3/Pd(OAc)2/Mo(CO)6 manifold as reported by
Larhed and co-workers17 in a single-mode microwave18
resulted in predominant formation of the dehalogenated
Ugi product 21, along with trace amounts of 12. A sim-
ilar pattern was observed when the reaction was per-
formed in a pre-heated oil-bath at 150 ꢁC for 15min.
The post-synthesis sample handling was fairly conve-
nient and application of the reaction mixture on to a cat-
ion-exchange resin (Bond ElutTM SCX),21 followed by
elution with CH3OH resulted in retention of the dehalo-
genated product as well as n-Bu3N, allowing for facile
purification of the macrolactam.
O
HN
N
O
HN
In conclusion, the synthesis of novel eight and nine-
membered lactams with multiple sites of diversity has
21

1700
A. Vasudevan, M. K. Verzal / Tetrahedron Letters 46 (2005) 1697–1701
18. (a) Larhed, M.; Hallberg, A. J. Org. Chem. 1996, 61, 9582;
(b) Strauss, C. R. Aust. J. Chem. 1999, 52, 83; (c) Tan, K.
L.; Vasudevan, A.; Bergman, R. G.; Ellman, J. A.; Souers,
A. J. Org. Lett. 2003, 5(12), 2131; (d) Larhead, M.;
Hallberg, A. Drug Discov. Today 2001, 6, 406; (e)
Commercial vendors of single-mode microwave instru-
mentation include Biotage AB (www.biotage.com) and
CEM corporation (www.cem.com). All microwave exper-
iments were performed in a CEM Explorerꢂ.
been accomplished via a carbonylation/intramolecular
amidation22 of the product of an Ugi MCR.
Acknowledgements
The encouragement of Dr. Stevan W. Djuric and assis-
tance of the structural chemistry group is appreciated.
19. Wu, X.; Mahalingam, A. K.; Wan, Y.; Alterman, M.
Tetrahedron Lett. 2004, 45, 4635.
References and notes
20. In all these experiments, similar results were observed
using (pre-heated) oil-bath conditions and single-mode
microwave irradiation. Performing the intramolecular
amidation in a sealed tube for up to 24 h did not afford
increased product formation compared to 1 h reaction
time. To avoid the potential of plating out of Mo (Ref. 17)
at elevated temperatures due to localized superheating in
the microwave, oil-bath conditions were prefered for these
transformations.
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21. Bond ElutTM SCX columns were purchased from Varian
Inc.
22. Typical procedure for the Ugi-deprotection–carbonyl-
ation/intramolecular amidation procedure: a solution of
1 equiv each of the amine, aldehyde, isocyanide and acid
(1 mmol each) in 3 mL anhydrous CH3OH was stirred at
room temperature for 18 h. The solvent was evaporated,
and the residue dissolved in 4 mL of 1:1 CH2Cl2–THF
followed by the addition of PS-TsNHNH2 (3 equiv) and
MP-CO3 (3 equiv). After stirring the reaction mixture for
4 h at room temperature, the reaction was filtered, and the
resin rinsed with CH2Cl2 (2 · 2 mL) and THF (2 · 2 mL).
The combined filtrate was concentrated to afford the pure
Ugi product. Treatment of the Ugi product with 4 mL 4 N
HCl/dioxane at room temperature for 6 h followed by
evaporation of the solvent afforded the pure deprotected
amine. The deprotected amine, Pd(OAc)2 (5mol %) and
Mo(CO)6 (0.5equiv) were weighed into a high-pressure
tube which was sealed and flushed with nitrogen. n-Bu3N
(3 equiv) and diglyme (1 mL) were added to the tube
which was immersed in an oil bath, preheated to 160 ꢁC.
At the end of 1 h, the reaction was cooled, the reaction
mixture filtered through a 0.5 lM syringe filter, and the
solvent evaporated. The residue was dissolved in 1 mL
TM
CH3OH and passed through a Bond Elut SCX column
(5g) and the first three rinses of 1 mL each were collected
to afford the desired macrolactam. Purification of the
combined washes, after evaporation, via flash chromato-
graphy afforded the desired macrolactam. Data for
selected compounds: 8: viscous light brown oil. 1H
NMR (300 MHz, DMSO-d6): d 8.02 (s, 1H), 7.95(d,
1H), 7.87 (br s, 2H), 7.48 (t, 1H), 7.36 (t, 1H), 7.23(d, 1H),
7.02–7.15 (m, 4H), 5.17 (s, 1H), 3.81 (s, 3 H), 3.53–3.46 (m,
1H), 3.10–3.04 (m, 1H), 2.93–2.86 (m, 1H), 2.60–2.53 (m,
1H), 1.28 (s, 9H). 13C NMR (300 MHz, DMSO-d6): d
172.37, 169.85, 158.82, 140.21, 137.85, 137.52, 130.35,
129.16, 128.67, 119.21, 115.22, 113.27, 111.74, 102.25,
69.10, 55.34, 50.79, 41.69, 36.71, 27.95. Compound 10:
viscous colorless oil. 1H NMR (300 MHz, DMSO-d6,
T = 120 ꢁC): d 8.14 (br s, 1H), 7.97 (dd, 1H), 7.46 (dt, 1H),
7.33 (dd, 1H), 7.13 (dt, 1H), 5.92 (s, 1H), 3.63–3.70 (m,
2H), 3.11–3.02 (m, 1H), 2.98–2.90 (m, 2H), 2.61–2.53 (m,
2H), 1.80–1.53 (m, 5H), 1.36–1.12 (m, 6H), 0.92–0.74 (m,
4H). 13C NMR (300 MHz, DMSO): d 174.32, 173.51,
169.20, 169.14, 140.41, 140.11, 138.57, 137.55, 130.72,
130.46, 130.37, 129.21, 128.96, 103.09, 102.64, 67.27,
65.51, 48.28, 48.23, 42.57, 41.91, 37.54, 32.23, 32.18,
32.08, 25.30, 24.75, 24.63, 24.53. Compound 11: viscous
pale brown oil. 1H NMR (300 MHz, DMSO-d6): d 8.25(s,
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12. PS-trisamine was purchased from Argonaut Technologies.
13. MP-CO3 was purchased from Argonaut Technologies.
14. (a) Schoenberg, A.; Bartoletti, I.; Heck, R. F. J. Org.
Chem. 1974, 39, 3318; (b) Schoenberg, A.; Heck, R. F.
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A. Vasudevan, M. K. Verzal / Tetrahedron Letters 46 (2005) 1697–1701
1701
2H), 7.98 (s, 1H), 7.84 (br d, 1H), 7.81 (d, 1H), 7.10 (t,
1H), 6.90–6.83 (m, 4H), 6.65(br s, 1H), 6.07 (s, 3H),3.41
(d, 1H), 3.17 (d, 1H), 1.27 (s, 9H). 13C NMR (300 MHz,
DMSO-d6): d 168.10, 166.06, 158.78, 139.15, 137.70,
131.74, 130.62, 130.30, 129.75, 129.63, 104.30, 68.16,
66.29, 55.14, 50.60, 28.39. Compound 17: white solid. H
NMR (300 MHz, DMSO-d6): d 8.52 (t, 1H), 8.39 (s, 1H),
7.66 (d, 1H), 7.62–7.56 (m, 2H), 7.48 (t, 1H), 7.36–7.31 (m,
3H), 7.08–7.04 (m, 1H), 5.31 (s, 1H), 3.98–3.92 (m, 1H),
3.75 (s, 3H), 3.63–3.55 (m, 1H), 3.51–3.39 (m, 2H), 1.28 (s,
9H). 13C NMR (300 MHz, DMSO-d6): d 168.36, 166.17,
166.03, 159.07, 142.18, 135.94, 131.73, 131.55, 129.31,
128.39, 122.71, 122.17, 119.30, 116.78, 112.44, 63.63,
55.17, 50.86, 40.81, 37.67, 28.28.
1