Design and synthesis of α-aminonitrile-functionalized novel retinoids

Article abstract of DOI:10.1016/j.tetlet.2009.07.119

We have developed an expedient one-pot method for the synthesis of α-aminonitrile-functionalized new retinoids via a three-component condensation of β-cyclocitral, amine, and TMSCN (trimethyl silylcyanide) in the presence of a catalytic amount of indium(I

Full text of DOI:10.1016/j.tetlet.2009.07.119

Tetrahedron Letters 50 (2009) 5670–5672
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Tetrahedron Letters
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Design and synthesis of a-aminonitrile-functionalized novel retinoids
b
b
Bhaskar C. Das a,b, , Jaime Anguiano , Sakkarapalayam M. Mahalingam
*
a Department of Nuclear Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA
b Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
We have developed an expedient one-pot method for the synthesis of a-aminonitrile-functionalized new
Received 9 April 2009
Revised 18 July 2009
Accepted 21 July 2009
Available online 25 July 2009
retinoids via a three-component condensation of b-cyclocitral, amine, and TMSCN (trimethyl silylcya-
nide) in the presence of a catalytic amount of indium(III) chloride in water. The reactions proceeded
smoothly at room temperature in water to generate the corresponding retinoids in moderate to excellent
yields (85–92%). In addition, the utility of this reaction was demonstrated to synthesize boron-containing
retinoids.
Keywords:
Retinoids
Ó 2009 Elsevier Ltd. All rights reserved.
a-Aminonitrile
Pinacolatoborane
Boron-containing retinoids
All trans retinoic acid (ATRA) and its metabolites play a crucial role
in adult physiological functions such as promoting growth and differ-
entiation, regulating apoptosis, and maintaining homeostasis in
numerous tissues and also play a crucial role in a variety of processes
such as patterning of anterior–posterior axis and development of
heart, brain, and limbs.1,2 ATRA is being used in differentiation ther-
apy of cancer, in cancer chemoprevention, and for the treatment of
dermatological diseases, including acne, psoriasis, and ichthyosis.3
Recently, ATRA has proven useful in cancer chemotherapy.4a One of
the mostimpressive effects of ATRAison acutepromyelocytic leukae-
mia (APL).4b The success of RA treatment is limited due to its rapid
degradationinthebodythatleadstonon-specifictoxicityandretinoic
acidsyndrome. Sothediscoveryofretinoidswithresistancetometab-
olism and/or restricted activity on different receptors is an active area
of research. For our ongoing chemical biology project, we have long-
term goal to develop new antagonist and agonist compounds in order
to target specific pathways to identify new gene targets of these path-
ways. Towardthisgoal,wefocusedonretinoicsignalingpathway,asit
plays key roles in patterning the body axis and in the formation of
many organs and defects in this signaling pathway cause many dis-
compounds synthesized, much attention has been paid to boronic
acid-containing peptides such as Velcade and DPP-IV inhibitors.8 In
these boropeptides, a carboxylic acid has been replaced by a boronic
acid group.
As
a-aminonitrile functionalities are significantly important
intermediates11 for the synthesis of a wide variety of amino acids,
amides, diamines, and nitrogen-containing heterocycles, we
hypothesized that introduction of a-aminonitrile moieties to syn-
thesize novel retinoid libraries may increase the efficacy and po-
tency in ATRA therapy and also help to study the RA signaling
biology to identify new biomarkers in this pathway. For this rea-
son, we planned to synthesize compounds 2–4 as new retinoic acid
analogues by introducing a phenyl ring in place of alkene spacers
(Fig. 1) and also the alkene functionalized as imine and its a-ami-
nonitrile derivatives by keeping hydrophobic part (cycloalkene)
and carboxylic acid intact.
alkene spacer
carboxylic
acid
eases.5 In this Letter, we report the synthesis of
taining novel retinoids and used this procedure to synthesize
boron-containing -aminonitrile-functionalized retinoids. Boron-
a-aminonitrile-con-
Me
Me
O
1
7
11
6
2
3
15 OH
9
13
14
10
8
12
a
5
4
containing retinoids are completely new class of retinoids, and may
open new avenue to study retinoic acid signaling biology. The use of
boronatomsinpharmaceuticaldrugdesignpossessesahighpotential
for discovery of new biological activity.6–10 Among various boron
hydrophobic
1: ATRA
O
B
COOH
COOH
H
O
CN
CN
N
N
H
N
H
2
3
4
* Corresponding author. Tel.: +1 718 430 2422; fax: +1 718 430 8853.
E-mail address: bdas@aecom.yu.edu (B.C. Das).
Figure 1. Structure of ATRA and new retinoids.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.119

B. C. Das et al. / Tetrahedron Letters 50 (2009) 5670–5672
5671
Table 1
Synthesis of
To synthesize new retinoids 3 and 4 and further functionalize
into new derivatives, we chose the cyanation of the imine scaffold
a-aminonitrile-functionalized retinoic acid analogues 3 by the reaction
a
of b-cyclocitral 5 with amines 6 and TMSCN in presence of catalytic amount of InCl3
2 (Fig. 1) as the key step to synthesize the
a-aminonitrile-function-
O
TMSCN
alized constrained new retinoids. The latter substrates bear an
a
-
CN
R
InCl (10 mol%)
3
R
H
aminonitrile moiety, which to the best of our knowledge has not
been reported previously in this system. More recently, indium(III)
compounds have been demonstrated to be mild, efficient, and
water-tolerant Lewis acids for various organic transformations.12
In contrast to classical Lewis acids, which often are required in
stoichiometric quantities, indium(III) compounds readily promote
a wide variety of organic reactions in catalytic quantities soluble
both in organic solvents and in aqueous media. We chose indiu-
m(III) chloride (InCl3) as the Lewis acid catalyst for the synthesis
+
N
H2N
H
H O, r.t.
2
Entry
Amine (6a–h)
Product (3a–h)
Yieldb (%)
CO2Me
CN
1
86
82
80
78
93
90
85
92
H2N
H2N
H2N
H2N
H2N
H2N
CO2CH3
N
H
of
a-aminonitrile-functionalized new retinoids.
In our preliminary experiments, we investigated the optimiza-
CN
2
3
4
5
6
7
tion of reaction conditions regarding both the catalyst and solvent.
We concentrated only b-cyclocitral 5 because this is the most
important part in ATRA as hydrophobic part as shown in Figure 1
N
H
and our objective was to keep this part intact and introduce a-ami-
Cl
F
CN
nonitrile and phenyl ring system as polyene chain spacer in ATRA.
For this purpose, b-cyclocitral 5 and methyl-4-amino benzoate
6a were chosen as model substrates for the synthesis of represen-
tative compound 3a (Scheme 1).
Cl
F
N
H
CN
The reaction took place efficiently at room temperature in water
and furnished the desired product 3a in 86% yield (Scheme 1) as a
white solid. The product was filtered and washed with water and
hexane to isolate it in an analytically pure form without column
chromatography. 1H, 13C, and HRMS corroborate the formation of
N
H
I
CN
the a
-aminonitrile-functionalized retinoid 3a.13
I
N
H
Although the use of an InCl3 as a catalyst permits facile recycle
with the aqueous phase. To demonstrate catalyst recovery without
loss of activity, we performed an experiment to reuse the catalyst
after the filtration of the product 3a. We used the same aqueous
phase for second set of reactions but the activity was reduced
and the reaction was not complete even after stirring the reaction
mixture at room temperature for 48 h and the isolated yield of 3a
was 52%.
Encouraged by above results, we continued our task of explor-
ing the reactivity of different amines (Table 1, entries 6b–h) with
b-cyclocitral 5 and TMSCN under similar reaction conditions. Table
1 shows a number of examples of this chemistry. As shown in Table
1, all amines could efficiently undergo reactions with b-cyclocitral
5 and TMSCN to give the products in good to excellent yields (Table
1, entries 2–8). We have chosen variety of amines bearing electron-
donating and electron-withdrawing groups to synthesize new ret-
inoids. The amine substrates, such as p-iodo (3e: 93%, Table 1, en-
try 5), p-methoxy (3f: 90%, Table 1, entry 6), and 2-(4-amino-
phenyl)-ethanol (3h: 92%, Table 1, entry 8) were obtained in higher
yields, and overall the process was convenient for synthesizing li-
brary of new class of retinoids. The experimental procedure is very
simple and generally involves mixing and stirring the three com-
ponents together at ambient temperature in presence of catalytic
amount of InCl3 for 4–6 h.
OMe
OH
CN
OMe
OH
N
H
CN
H2N
H2N
N
H
OH
CN
8
N
H
OH
a
All reactions were performed using 1 equiv of aldehyde and 1 equiv of amine
and 1.2 equiv of TMSCN in water 4–6 h.
b
Isolated yield refers to aldehyde.
After generalizing the procedure, we turned our attention to-
ward the synthesis of boron-containing a-aminonitrile-functional-
ized retinoid 4. In this case, b-cyclocitral 5 was treated with 4-
aminophenylboronic acid pinacol ester 7 in the presence of cata-
lytic amount of InCl3 and TMSCN and the desired boron-containing
retinoid 4 was isolated in 88% yield (Scheme 2). From literature
A typical solvent is water although water/methanol mixture can
also be used. It is noteworthy that the reaction does not require
anhydrous or oxygen-free conditions and is also readily adaptable
to synthesis for the construction of combinatorial libraries to scale-
up. All the products were isolated as air-stable white solids.
search, we found this to be the first example where
a-aminoni-
trile-functionalized boron-containing retinoids were synthesized.
In summary, we have developed an expedient one-pot method
for the synthesis of new class of constrained retinoids (b-cycloci-
tral-derived a-aminonitriles) via a three-component condensation
NH2
O
CO2Me
TMSCN
InCl (10 mol%)
3
of b-cyclocitral, amine, and TMSCN in the presence of a catalytic
amount of indium(III) chloride in water. This method is quite gen-
eral and it works well with a wide variety of amines at room tem-
perature. This method is simple and attractive for synthesizing
highly important small molecular retinoid libraries. This is the first
CN
H
+
N
H O, r.t.
H
2
CO2Me
6a
3a; 86%
5
Scheme 1. Synthesis of
a
-aminonitrile-functionalized retinoids.
example where we synthesized boron- and a-aminonitrile-con-

5672
B. C. Das et al. / Tetrahedron Letters 50 (2009) 5670–5672
S. M.; Evans, T.; Kabalka, G. W.; Anguiano, J.; Hema, K. Chem. Commun. 2009,
NH2
O
O
B
2133.
TMSCN
InCl3 (10 mol%)
H
6. Groziak, M. P.. In Progress in Heterocyclic Chemistry; Gribble, G. C., Gilchrist, T. L.,
Eds.; Pergamon: Oxford, 2000; Vol. 12, pp 1–21.
O
+
CN
H2O, r.t.
N
7. (a) Morin, C. Tetrahedron 1994, 50, 12521; (b) Yang, W.; Gao, X.; Wang, B. Med.
Res. Rev. 2003, 23, 346.
B
O
H
5
O
7
4; 88%
8. (a) Matteson, D. S. Tetrahedron 1989, 45, 1859; (b) Matteson, D. S. Chem. Rev.
1989, 89, 1535; (c) Tian, Z.-Q.; Brown, B. B.; Mack, D. P.; Hutton, C. A.; Bartlett,
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(e) Skordalakes, E.; Eligendy, S.; Goodwin, C. A.; Green, D.; Scully, M. F.; Kakkar,
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Scheme 2. Synthesis of boron-containing retinoid 4.
taining retinoids. In future this will open a new avenue, in retinoic
acid signaling pathways to identify new biomarkers, which may be
used as therapeutic agents for diseases induced by RA pathways.
Experiments are currently underway to test the biological activity
of these derivatives and to determine their utility as modulators of
retinoic acid signaling pathways.
10. (a) Das, B. C.; Mahalingam, S. M.; Evans, T. Tetrahedron Lett. 2009, 50, 3031; (b)
Kabalka, G. W.; Das, B. C.; Das, S. Tetrahedron. Lett. 2001, 42, 7145.
11. (a) Shafran, Y. M.; Bakulev, V. A.; Mokrushin, V. S. Russ. Chem. Rev. 1989, 58,
148; (b) Duthaler, R. O. Tetrahedron 1994, 50, 1539; (c) Matier, W. L.; Owens, D.
A.; Comer, W. T.; Deitchman, D.; Ferguson, H. C.; Seidehamel, R. J.; Young, J. R. J.
Med. Chem. 1973, 16, 901; (d) Dyker, G. Angew. Chem., Int. Ed. 1997, 36, 1700;
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Synlett 1995, 1087; (d) Podlech, J.; Maier, T. C. Synthesis 2003, 633; (e) Nair, V.;
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Org. Chem. 2000, 2347; (g) Auge, J.; Lubin-Germain, N.; Uziel, J. Synthesis 2007,
1739; (h) Ranu, B. C.; Dey, S. S.; Hajra, A. Tetrahedron 2002, 58, 2529; (i) Das, B.;
Damodar, K.; Shashikanth, B.; Srinivas, Y.; Kalavathi, I. Synlett 2008, 3133; (j)
Shen, Z. L.; Ji, S. J.; Loh, T. P. Tetrahedron 2008, 64, 8159.
13. General procedure for the synthesis of retinoids (Table 1): Into a 10-mL round-
bottomed flask were added b-cyclocitral (1.0 mmol), amine (1.0 mmol), TMSCN
(1.2 mmol), H2O (2 mL), and InCl3 (0.1 mmol) sequentially. The reaction
mixture was stirred vigorously at room temperature and the progress of the
reaction was monitored by TLC. After stirring for 4–6 h at room temperature
the solid that was obtained was filtered and washed with water and hexane to
yield the desired product retinoids (4a–h and 7).
Acknowledgment
The author B.C.D. is thankful to AECOM for start up funding.
Supplementary data
Supplementary data (Experimental procedures and copies of 1H,
13C NMR) associated with this article can be found, in the online
version, at doi:10.1016/j.tetlet.2009.07.119.
References and notes
Compound 3a: Rf = 0.61 (ethyl acetate/hexane = 1:2); 1H NMR (300 MHz,
CDCl3): d 0.95 (s, 3H), 1.16 (s, 3H), 1.45–1.70 (m, 4H), 2.03 (s, 3H), 2.07–2.09
(m, 2H), 3.89 (s, 3H), 4.08–4.09 (d, J = 3 Hz, 1H), 4.71–4.73 (d, J = 6 Hz, 1H),
6.72–6.75 (d, J = 9 Hz, 2H), 7.96–7.99 (d, J = 9 Hz, 2H) ppm; 13C NMR (75.4 MHz,
CDCl3): d 168.0, 149.8, 139.3, 134.8, 132.1, 122.2, 119.0, 112.6, 52.3, 43.8, 39.0,
35.7, 34.4, 28.8, 27.6, 21.9, 19.3 ppm; HRMS (EI, m/z): [M+H]+, calcd for
C19H25N2O2: 313.1916, found: 313.1922.
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Compound 4: Rf = 0.65 (ethyl acetate/hexane = 1:2); 1H NMR (300 MHz, CDCl3):
d 0.94 (s, 3H), 1.15 (s, 3H), 1.35 (s, 12H), 1.40–1.70 (m, 4H), 2.03 (s, 3H), 2.05–
2.14 (m, 2H), 3.83–3.84 (d, J = 3 Hz, 1H), 4.70–4.72 (d, J = 6 Hz, 1H), 6.72–6.75
(d, J = 9 Hz, 2H), 7.73–7.76 (d, J = 9 Hz, 2H) ppm; 13C NMR (75.4 MHz, CDCl3): d
149.2, 137.0, 136.9, 133.8, 120.2, 112.7, 83.8, 44.5, 39.2, 36.4, 34.0, 28.5, 27.9,
25.3, 25.2, 21.8, 18.9 ppm; HRMS (EI, m/z): [M+Na]+, calcd for C23H33BN2NaO2:
403.2533, found: 403.2543.