Cyclic products of the Ugi reaction of aldehydo and keto carboxylic acids: Chemoselective modification

Article abstract of DOI:10.1016/j.tetlet.2011.02.028

A method for the chemoselective reduction of Ugi-type lactam amides at the lactam carbonyl functionality with borane complexes has been developed. The novel reduction products can be further manipulated synthetically to yield various novel N- and C-termin

Full text of DOI:10.1016/j.tetlet.2011.02.028

Tetrahedron Letters 52 (2011) 1800–1803
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Cyclic products of the Ugi reaction of aldehydo and keto carboxylic acids:
chemoselective modification
Alan Tsaloev a, Alexei Ilyin a, Sergey Tkachenko b, Alexandre Ivachtchenko a,b, Dmitry Kravchenko a,
Mikhail Krasavin a,c,
⇑
a Chemical Diversity Research Institute, 2a Rabochaya St., Khimki, Moscow Reg. 141400, Russia
b ChemDiv, Inc., 6605 Nancy Ridge Drive, San Diego, CA 92121, USA
c Science and Education Center ‘Innovative Research’, Yaroslavl State Pedagogical University, Yaroslavl 150000, Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
A method for the chemoselective reduction of Ugi-type lactam amides at the lactam carbonyl function-
ality with borane complexes has been developed. The novel reduction products can be further manipu-
lated synthetically to yield various novel N- and C-terminally active unnatural amino acid building
blocks.
Received 3 January 2011
Revised 25 January 2011
Accepted 4 February 2011
Available online 23 February 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Ugi reaction
Bifunctional reagents
Chemoselective reduction
Unnatural amino acids
1. Introduction
amines into N- and C-terminally active unnatural amino acid
building blocks.
Replacement of two participants in the Ugi four-component
reaction with a single bifunctional reagent has proved itself a fruit-
ful strategy towards various drug-like heterocycles.1 Specifically,
various tethered keto (or aldehydo) carboxylic acids, when em-
ployed in the Ugi process, provide a facile (and high-yielding) entry
into diverse lactam amides (Fig. 1). Since the initial publications
describing this methodology by Harriman2 and Ugi3 in the late
1990s, a significant number of these peptidomimetic scaffolds have
appeared in the literature. This, in turn, resulted in extensive inves-
tigations on the associated biological activities which have yielded
promising leads for modulation of important biological targets
2. Results and discussion
A set of 22 3-oxo-2,3,4,5-tetrahydro-1,4-benzoxazepine-5-car-
boxamides 1a–x (Scheme 1) was prepared in good to excellent
yields from the known 2-(2-formylphenoxy)acetic acid6 using var-
ious amines and two isocyanides as described earlier.7 Inspired by
the successful application of borane complexes for reduction of lin-
ear Ugi reaction derived diamides, as recently disclosed by Tron,8
we exposed lactam amides 1a–x to an excess of borane–dimethyl
sulfide complex in THF at room temperature (Scheme 1). To our
delight, in all cases, this led to a clean and complete reduction of
the lactam function only, with no trace of secondary amide reduc-
such as androgen receptors4 and -secretase.5
c
We have been involved in identifying opportunities for chemo-
selective modification of these intriguing drug-like scaffolds, in
pursuit of a dual goal: (i) improving the physicochemical proper-
ties of lactam amides (specifically, their aqueous solubility) and
(ii) preparing functionalized peptidomimetic building blocks based
on these scaffolds which are useful in designing yet more novel
compound libraries for biological screening. Herein, we report sev-
eral examples of efficient, chemoselective reduction of such lactam
amides and further transformation of the resulting cyclic tertiary
O
R1
O
4-center, 3-component
N
OH
O
Ugi reaction
R
linker
linker
R2
R1NH2, R2NC
R
O
N
H
R = alkyl or H
⇑
Corresponding author. Tel.: +7 495 995 4944; fax: +7 495 626 9780.
E-mail address: myk@chemdiv.com (M. Krasavin).
Figure 1. Cyclic lactam amides resulting from the Ugi reaction of bifunctional keto
(aldehydo) carboxylic acids.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.02.028

A. Tsaloev et al. / Tetrahedron Letters 52 (2011) 1800–1803
1801
tion, even on prolonged (3 days) treatment at room temperature
(heating of selected reaction mixtures to reflux ultimately led to
the accumulation of the double-reduction material, however, this
was never characterized due to difficulties in its isolation). The sta-
ble tertiary amine–borane complex immediately resulting from
such reductions was destroyed by briefly refluxing the crude reac-
R2
NH
R2
NH
1) BH3·SMe2 (4 eq.)
O
O
R1
THF, r. t.
16-20 h
R1
R1NH2, R2NC
O
N
N
O
OH
MeOH, 50 oC
2-3 h
2) sat. HCl/MeOH
reflux, 30 min
O
O
O
O
1a-x
6a-x
Scheme 1. Ugi reaction of 2-(2-formylphenoxy)acetic acid and chemoselective reduction of the resulting lactam amides 1a–x.
Table 1
Preparation and chemoselective reduction of the lactam amides 1a–x (Scheme 1)
Entry
R1
R2
Yield of 1 (%)
LC–MS [M+H+] m/z
Yield of 6 (%)
LC–MS [M+H+] m/z
1(6)a
1(6)b
1(6)c
1(6)d
1(6)e
1(6)f
1(6)g
1(6)h
1(6)i
n-Pr
i-Pr
i-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
4-CF3C6H4CH2
4-CF3C6H4CH2
4-CF3C6H4CH2
4-CF3C6H4CH2
4-CF3C6H4CH2
4-CF3C6H4CH2
4-CF3C6H4CH2
4-CF3C6H4CH2
4-CF3C6H4CH2
4-CF3C6H4CH2
4-CF3C6H4CH2
4-CF3C6H4CH2
60
64
51
68
86
74
66
46
54
56
72
66
67
52
43
74
86
58
74
69
55
82
79
47
305.6
305.7
319.7
349.2
303.5
331.4
359.8
367.1
381.6
427.5
353.5
387.5
407.5
407.5
420.6
451.3
405.6
433.3
461.7
469.4
483.5
529.5
455.6
489.6
78
50
53
56
81
74
63
57
63
70
82
51
71
89
93
65
94
67
54
67
65
75
56
71
291.4
291.3
305.7
335.6
289.5
317.2
345.8
353.7
367.7
413.2
339.5
373.8
393.6
393.3
407.6
437.6
391.5
419.5
447.7
455.6
469.6
515.4
441.7
475.9
EtO(CH2)3
Cyclopropyl
Cyclopentyl
Cycloheptyl
Ph(CH2)2
4-MeC6H4(CH2)2
3,4-(MeO)2C6H3(CH2)2
Bn
1(6)j
1(6)k
1(6)l
4-ClC6H4CH2
n-Pr
i-Pr
1(6)m
1(6)n
1(6)o
1(6)p
1(6)q
1(6)r
1(6)s
1(6)t
1(6)u
1(6)v
1(6)w
1(6)x
i-Bu
EtO(CH2)3
Cyclopropyl
Cyclopentyl
Cycloheptyl
Ph(CH2)2
4-MeC6H4(CH2)2
3,4-(MeO)2C6H3(CH2)2
Bn
4-ClC6H4CH2
O
OH
S
N
N
S
N
N
O
b
a
O
O
O
O
N
S
HN
O
HN
O
O
O
O
2
3, 57%
7, 84%
b
a
O
OH
N
N
N
N
N
N
N
N
O
H
H
N
N
O
O
O
8, 45%
5, 61%
4
Scheme 2. Preparation and chemoselective reduction of lactam amides 3 and 5. Reagents and conditions: (a) t-BuNC (1.2 equiv), BnNH2 (1.0 equiv), MeOH, 50 °C, 3 h; (b)
BH3ÁSMe2 (4.0 equiv), THF, rt, 18 h; satd MeOH–HCl, reflux, 30 min.

1802
A. Tsaloev et al. / Tetrahedron Letters 52 (2011) 1800–1803
R2
NH
R2
NH
OH
NH
O
O
R1
O
O
6e, 65%
6f, 71%
6k, 80%
R1
NaBH4, I2
48% HBr in AcOH
130 oC, 16 h
. HBr
N
N
N
N
O
THF
0 oC --> r. t.
16 - 22 h
O
O
O
O
1e,f,k
11a, 98%
6c
Scheme 3. Chemoselective reduction of selected lactam amides 1 using the NaBH4–
I2 protocol.
OH
O
NH
O
R1
. HCl
R1
conc. HCl
tion mixture in saturated methanolic HCl. The product 2,3,4,5-tet-
rahydro-1,4-benzoxazepine-5-carboxamides 6a–x were isolated
chromatographically in good to excellent yields (Table 1). A nota-
ble feature of these hitherto unknown compounds 6 is that they
are close shape mimics of the peptidomimetic lactam amides 1
containing a basic nitrogen. Hence, they are expected to have bet-
ter aqueous solubility and the basic centre can be utilized for the
preparation of various salts (including diastereomeric salts for
enantiomer resolution)—both features having much appeal for
the development of drug candidates based on this novel scaffold.
Moreover, the utility of this chemoselective lactam reduction pro-
cedure can be extended to other lactam amides (3 and 5), also pre-
pared via the Ugi reaction of the keto acids 2 and 4, respectively.
The yield from the reduction of aromatic lactam 5 was low (45%)
while the aliphatic lactam 3 was reduced in an excellent 84% yield
(Scheme 2).
N
N
reflux, 16-22 h
O
O
11b, R1 = cyclopropyl, 96%
11c, R1 = benzyl, 98%
6e, 6k
Scheme 5. tert-Butyl amide hydrolysis.
In summary, we have described some new evolutionary direc-
tions for Ugi reaction derived lactam amides to be developed into
novel, drug-like heterocyclic scaffolds and unnatural amino acid
building blocks.
3. General procedure 1: synthesis of lactam amides 1 (3 or 5)
The nature of the borane reducing agent seems unimportant for
the outcome of the lactam reduction. For example, the borane–THF
complex generated in situ from sodium borohydride and iodine9
reduced selected lactams 1 in yields similar to those obtained
using the BH3ÁSMe2 procedure (Scheme 3).
The aldehydo or keto carboxylic acid (1.0 equiv) and primary
amine (1.0 equiv) were dissolved in MeOH. The solution was stir-
red at rt for 10 min. The appropriate isocyanide (1.2 equiv) was
added and the resulting mixture was stirred at 50 °C for 2–3 h.
On completion, the reaction mixture was cooled to rt, and the
resulting precipitate was filtered, washed with MeOH, and purified
by crystallization from Et2O by chromatography on silica gel, using
an appropriate gradient of MeOH in CH2Cl2 as eluent.
Compounds 6 are, essentially, amides of unnatural
a-amino
acids. We were successful in removing a benzyl group from the
compounds 6k and 6w (with remarkable chemoselectivity with re-
spect to the second benzyl group in the latter case) and exposing
the secondary nitrogen atom in the resulting products 9a,b to fur-
ther modifications (for example, efficient reductive alkylation with
aldehydes or ketones, Scheme 4). Likewise, selected tert-butyl
amides 6c and 6e(6k), when treated with strong Brønsted acids
at reflux, furnished nearly quantitative yields of the novel cyclic
Compound 1a: white solid, mp = 130–132 °C. 1H NMR (400 MHz,
DMSO-d6): d 7.45 (d, J = 7.6 Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H), 7.07–7.05
(m, 2H), 6.94 (d, J = 8.0 Hz, 1H), 5.09 (d, J = 14.4 Hz, 1H), 4.99 (s, 1H),
4.19 (d, J = 14.4 Hz, 1H), 3.57 (m, 1H), 3.15–3.11 (m, 1H), 1.55–1.52
(m, 2H), 1.23 (s, 9H), 0.81 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz,
DMSO-d6): d 169.5, 168.1, 156.4, 130.3, 129.2, 127.5, 122.8, 119.9,
a-amino acids 11a–c, without disruption of the tetrahydro-1,4-
benzoxazepine ring (Scheme 5).
R2
NH
R2
NH
R2
NH
O
R1
aldehyde or ketone
O
H2 (1 atm.)
10% Pd-C
O
NaBH(OAc)3
H
N
N
N
1,2-dichloroethane
MeOH, r. t.
r. t., 1-8 h
O
O
O
9a, R2 = t-Bu, 88%
10a, R2 = t-Bu, R1 = 4-FC6H4CH2, 74%
6k, 6w
9b, R2 = 4-CF3C6H4CH2, 94%
10b, R2 = t-Bu, R1 = 1-acetylpiperidin-4-yl, 55%
10c, R2 = t-Bu, R1 = 1-Boc-piperidin-4-yl, 53%
10d, R2 = 4-CF3C6H4CH2, R1 = 4-FC6H4CH2, 66%
6b, R2 = t-Bu, R1 = i-Pr, 69%
6n, R2 = 4-CF3C6H4CH2, R1 = i-Pr, 78%
Scheme 4. N-Debenzylation of compounds 6k and 6w, and reductive alkylation of the resulting amines.

A. Tsaloev et al. / Tetrahedron Letters 52 (2011) 1800–1803
1803
72.4, 63.9, 50.6, 49.9, 28.1, 20.5, 11.0. Anal. Calcd for C17H24N2O3: C,
67.08; H, 7.95; N, 9.20. Found: C, 67.14; H, 8.01; N, 9.23.
02.740.11.0092). Dr. Alex Khvat and Dr. Volodymyr Kysil of Chem-
Div, Inc. (San Diego, USA) are acknowledged for helpful discussions
regarding the strategies for lactam reduction.
4. General procedure 2: reduction of lactam amides 1 (3 or 5)
Supplementary data
A solution of 1 (3 or 5) (1 mmol) in anhydrous THF (3 mL) was
treated with BH3ÁSMe2 in THF (2 M solution, 2 mL, 4 mmol). This
mixture was stirred overnight at rt after which the solvent was
evaporated and the residue was dissolved in satd MeOH–HCl.
The solution was heated at reflux for 30 min and after cooling to
rt, was neutralized with 10% aq K2CO3, and the resulting neutral
solution was extracted with CH2Cl2 (3 Â 50 mL). The combined or-
ganic extract was dried over anhydrous MgSO4, filtered and con-
centrated in vacuo. The residue was purified by preparative TLC
(silica gel, CH2Cl2).
Characterization data and preparative procedures for the newly
synthesized compounds (1a–x, 6a–x, 3, 5, 7, 8, 9a–b, 10a–d, 11a–c)
are available. Supplementary data associated with this article can
be found, in the online version, at doi:10.1016/j.tetlet.2011.02.028.
References and notes
1. For an excellent review of applications of bifunctional reagents in the Ugi
reaction, see: Hulme, C.; Dietrich, J. Mol. Divers. 2009, 13, 195–207. and
references cited therein.
Compound 6a: waxy-beige solid. 1H NMR (400 MHz, CDCl3): d
7.32 (s, 1H), 7.24–7.17 (m, 2H), 7.03 (t, J = 10.0 Hz, 1H), 6.97 (d,
J = 10.8 Hz, 1H), 4.27 (s, 1H), 4.09–3.98 (m, 2H), 3.12–3.04 (m,
1H), 2.90–2.82 (m, 1H), 2.48 (t, J = 8.0 Hz, 2H), 1.52 (m, 2H), 1.37
(s, 9H), 0.92 (t, J = 9.6 Hz, 3H). 13C NMR (100 MHz, CDCl3): d
169.7, 155.8, 130.8, 128.7, 123.1, 120.7, 70.0, 67.4, 54.9, 50.1,
49.6, 28.2, 20.4, 11.2. Anal. Calcd for C17H26N2O2: C, 70.31; H,
9.02; N, 9.65. Found: C, 70.28; H, 8.92; N, 9.55.
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3. Hanusch-Kompa, C.; Ugi, I. Tetrahedron Lett. 1998, 39, 2725–2728.
4. Rafferty, S. W.; Stewart, E. L.; Turnbull, P. S.; Yates, C. M. PCT Int. Appl.
WO2008121602; Chem. Abstr. 2008, 149, 425988.
5. Galley, G.; Goodnow, R. A.; Peters, J.-U. U.S. Patent Appl. Publ. US2004235819;
Chem. Abstr. 2004, 142, 6564.
6. Hullar, T. L.; Failla, D. L. J. Med. Chem. 1969, 12, 420–424.
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This research was supported by the Federal Agency for Science
and Innovation (Russian Federation Government Contract