Cross metathesis-mediated synthesis of hydroxamic acid derivatives

Article abstract of DOI:10.3762/bjoc.14.285

An alternative synthesis of α,?-unsaturated hydroxamates via cross metathesis between a class-I olefin and N-benzyloxyacrylamide is reported. The reaction proceeds better in the presence of Grubbs' second generation catalyst within short time and in good

Full text of DOI:10.3762/bjoc.14.285

Cross metathesis-mediated synthesis of
hydroxamic acid derivatives
Shital Kumar Chattopadhyay*, Subhankar Ghosh and Suman Sil
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2018, 14, 3070–3075.
Department of Chemistry, University of Kalyani, Kalyani - 741235,
West Bengal, India, Fax: +91+33+25828282
doi:10.3762/bjoc.14.285
Received: 01 August 2018
Accepted: 29 November 2018
Published: 17 December 2018
Email:
Shital Kumar Chattopadhyay* - skchatto@yahoo.com
*
Corresponding author
This article is part of the thematic issue "Progress in metathesis
chemistry III".
Keywords:
α-amino acid; catalysis; cross metathesis; hydroxamates
Guest Editors: K. Grela and A. Kajetanowicz
©
2018 Chattopadhyay et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
An alternative synthesis of α,ß-unsaturated hydroxamates via cross metathesis between a class-I olefin and N-benzyloxyacrylamide
is reported. The reaction proceeds better in the presence of Grubbs’ second generation catalyst within short time and in good yields
(
57–85%) with a range of substrates. Subsequent hydrogenation of each of the CM products delivers the title compounds in moder-
ate to very good yield (70–89%). An important demonstration of the protocol is the preparation of the unusual amino acid compo-
nent of the bioactive cyclic peptide Chap-31.
Introduction
Cross-metathesis reactions (CM) have rapidly grown [1-3] to be pounds of interest as well as for green chemical applications
a reliable method for the preparation of functionalized alkenes [21,22].
and derivatives thereof. Intricacies regarding the electronic
nature of olefins, their substitution patterns and steric demands Hydroxamates belong to a class of valuable biologically rele-
are more or less settled through the works of many workers in vant compounds of proven record of utility. For example, the
many reports [4-7]. Yet, a number of new reports describing the hydroxamate SAHA (1, Figure 1) [23] and the didehydrohy-
CM-mediated synthesis of functionalized alkenes of various droxamate TSA (2) [24], display useful anticancer properties
kinds continue to appear. For example, cross metathesis with through inhibition of histone deacetylase enzymes (HDAc) and
acrylates [8-10], α,ß-unsaturated acid chlorides [11], acryl- are used as FDA-approved drugs. Similarly, the cyclic peptide
amides [12-14], vinyl sulfones [15], vinylphosphine oxides Chap-31 (3) [25] with a terminal hydroxamic acid residue has
[
16], vinyl phosphonates [17], enones [18], and nitrile function- shown promising anticancer activity. Access to such deriva-
alities [19,20] have been shown to yield shorter routes to com- tives usually involves the preparation of the corresponding acid
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Beilstein J. Org. Chem. 2018, 14, 3070–3075.
Figure 1: Some bioactive molecules containing hydroxamate functionality.
and subsequent amide bond formation with hydroxylamines. phenylmethylene)ruthenium] (HG-II) was used under identical
Although this two-step protocol is widely used, a direct access conditions. Hydrogenation of the later in the presence of
to α,ß-unsaturated and saturated hydroxamates from cross me- Pd(OH)2/C proceeded uneventfully resulting in the saturation of
tathesis of alkenes may prove to be of advantage. In continua- the double bond as well as concommitant deprotection of the
tion of our earlier studies [26,27] on HDAC inhibitors, we O-benzyl group. The one-pot CM-hydrogenation sequence
herein report a direct access to α,ß-unsaturated hydroxamates using the same ruthenium catalyst has recently found applica-
through cross-metathesis reaction.
tions [28-30]. However, similar attempts in our case, i.e., direct
conversion of 4 + 5 → 7 proved to be problematic and conver-
sion to the desired product was not observed under the
Results and Discussion
It is known that a CM reaction between a class-I olefin and a attempted conditions. An intractable mixture of compounds was
class-II olefin proceeds better in the presence of 2nd generation the result.
catalysts. Accordingly, CM between 1-decene (4, R = C7H15)
and N-benzyloxyacrylamide 5 (Scheme 1) was attempted with Having established the conditions for stepwise CM and hydro-
Grubbs’ second generation catalyst [(1,3-bis(2,4,6-trimethyl- genation reactions, we extended the study to other substrates
phenyl)-2-imidazolidinylidene)dichloro(phenylmethylene) (Table 1). For example, the yields of the two steps for dodecene
(
tricyclohexylphosphine)ruthenium, G-II]. After some experi- forming 6b and 7b were more or less similar with those for
mentation, it was found that the reaction proceeds quickly in decene when either of the 2nd-generation catalysts was used.
refluxing dichloromethane to provide the CM product 6 However, analogous reaction with bromobutene 4c as CM
(
R = C7H15) in 81% yield. The yield of 6 was improved to 84% partner proceeded with some compromise in yield with G-II.
when Hoveyda–Grubbs 2nd generation catalyst [1,3-bis-(2,4,6- Moreover, HG-II in this case proved to be less successful. Simi-
trimethylphenyl)-2-imidazolidinylidene]dichloro(o-isopropoxy- larly, the allylbenzene derivatives 4d–f reacted with more or
Scheme 1: Cross metathesis between a class-I alkene and N-benzyloxyacryl amide.
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Table 1: Hydroxamates prepared.
Entry
Alkene 4
CM product 6 (% yield)
reduction product 7 (% yield)
1
4a
4b
4c
6
a (81)
b (85)
7a (85)
7b (83)
2
3
4
6
6
c (72)
d (77)
7c (70)
7d (89)
4
d
e
6
5
6
4
6
e (72)
7e (85)
7f (80)
4f
6f (78)
7
4
g
h
6
g (57)
7g (83)
7h (81)
7i (78)
7j (75)
8
9
4
6h (79)
4
i
6
i (73)
10
11
12
4
j
6
j (70)
4
k
6
k (78)
7k (86)
7l (84)
4
l
6
l (78)
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Beilstein J. Org. Chem. 2018, 14, 3070–3075.
less similar ease with G-II to produce the corresponding CM Grubbs’ second generation catalyst G-II (10 mg, 2 mol %), was
products 6d–f, respectively. Considerable isomerization (1:1 by added to a stirred solution of the olefin 4a (158 mg,
1
H NMR) of the CM-product 6d to the corresponding styrene 1.13 mmol), and olefin 5 (100 mg, 0.56 mmol), in anhydrous
derivative was noticed when HG-II was used in place of G-II. and degassed CH2Cl2 (3 mL) at rt and the reaction mixture was
e behaved similarly. Reaction with the styrene derivative 4g heated to reflux for 6 h under argon atmosphere. The reaction
6
resulted in low conversion to the CM product 6g (57%). Styrene mixture was allowed to cool to room temperature and then
derivatives, belonging to class-I olefins according to Grubbs’ concentrated in vacuo. The residue was purified by column
generalizations [31], are indeed known to be a sluggish partner chromatography on silica gel (hexane/ethyl acetate 60:40) to
in CM reactions, with homodimerization to stilbene being a provide the CM product (E)-N-benzyloxy)undec-2-enamide (6a,
recurring problem.
133 mg, 81%) as a colourless viscous liquid.
Alkenes 4h–j containing a benzyl ester functionality at two, IR (neat): 3183, 3064, 2926, 2855, 1669, 1683 cm−1; 1H NMR
three and four carbons apart, respectively, participated in the (400 MHz, DMSO-d6) δ 11.15 (s, 1H, NH,), 7.38–7.29 (m, 5H,
reaction nearly equally well to give the corresponding CM ArH), 6.74–6.67 (m, 1H, C3-H), 5.72 (d, J = 15.2 Hz, 1H,
products 6h–j. Hydrogenation of each of these compounds C2-H), 4.80 (s, 2H, OCH2-), 2.08 (q, J = 6.8 Hz, 2H, C4-H),
separately led to the corresponding saturated hydroxamic acid 1.33 (brs, 3H, CH2), 1.12 (s, 12H, CH2), 0.81 (t, J = 6.8 Hz, 3H,
derivatives 7h–j with concommittant cleavage of the terminal C11-H3); 13C NMR (100 MHz, DMSO-d6) δ 163.4 (CO), 144.3
benzyl ester functionality. In an extension to the synthesis of the (C3), 136.4 (ArC), 129.2 (ArCH), 128.7 (ArCH), 121.1 (C2),
unusual amino acid component of the important anticancer 77.4 (OCH2), 31.8 (C4), 31.7 (C5), 29.3 (CH2), 29.1 (CH2),
cyclic peptide compound Chap-31, we attempted the cross-me- 29.0 (CH2), 28.2 (CH2), 22.6 (CH2), 14.3 (C11); HRMS (TOF
tathesis reaction of N-benzyloxyacryl amide 5 with the homoal- MS ES+) m/z: [M + Na]+ calcd for C18H27NNaO2, 312.1939;
lylglycine derivative 4k (Table 1, entry 11) and the bis- found, 312.1956.
homoallyl glycine derivative 4l (Table 1, entry 12) [32], sepa-
rately. Fortunately, both the reactions proceeded well and the General procedure for hydrogenation
desired amino acid derivatives 7k and 7l were obtained in good
yields after hydrogenation.
Conclusion
In conclusion, we have developed a direct access to functionali-
zed hydroxamic acid derivatives using a cross-metathesis reac-
tion between N-benzyloxyacylamide and a range of terminal
alkenes. The products include hydroxamic acid derivatives with CM product 6a (50 mg, 0.17 mmol) was taken in a MeOH
a long alkyl chain, aromatic and heteroaromatic cores, halogen (3 mL) containing 1 drop of TFA [33]. Then Pd(OH)2 (10 mg)
residue, carboxylic acid moiety at the terminal relevant position was added and the solution was degassed several times. Hydro-
for drug discovery. Moreover, an alternate preparation of the gen gas was let in and the resulting heterogeneous mixture was
amino acid component of the important cyclic peptide Chap-31 vigorously stirred at atmospheric pressure for 2 h. It was filtered
may encourage the preparation of cyclic peptide based HDAC through Celite, the filter cake was washed with methanol
inhibitors. The developed methodology may hence complement (5 mL) and the combined filtrate was concentrated in vacuo.
the existing literature on the preparation of such class of com- The residue was purified by column chromatography on silica
pounds and may find applications.
gel (CHCl3/MeOH 97:3) to provide the product N-hydroxyun-
decanamide 7a (85%) as a colorless solid.
Experimental
General procedure for cross metathesis
Mp 85 °C; IR (neat): 3259, 3058, 2956, 1663, 1624 cm−1;
1
H NMR (400 MHz, DMSO-d6) δ 10.52 (s, 1H, NH), 8.93 (brs,
1
1
H, OH), 1.92 (t, J = 7.2 Hz, 2H, C2-H), 1.44 (m, 2H, C3-H),
.19 (s, 14H, 7× CH2), 0.81 (t, J = 6.8 Hz, 3H, C11-H);
1
3C NMR (100 MHz, DMSO-d6) δ 170.4 (CO), 32.6 (C2), 31.6
(
(
[
C3), 29.3 (CH2), 29.3 (CH2), 29.1 (CH2), 28.9 (CH2), 25.5
CH2), 22.5 (CH2), 14.3 (C11); HRMS (TOF MS ES+) m/z:
M + Na]+ calcd for C11H23NNaO2, 224.1626; found,
2
24.1638.
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Beilstein J. Org. Chem. 2018, 14, 3070–3075.
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