The first total synthesis of galloyl tyramine

Article abstract of DOI:10.1515/znb-2009-0419

The first total synthesis of galloyl tyramine, an inhibitor of Pim2 kinase was accomplished in an overall high-yield reaction sequence.

Full text of DOI:10.1515/znb-2009-0419

464
Note
Recently bioassay-guided fractionation of an or-
ganic extract of the rainforest tree Cupaniopsis macro-
petala Radlk. (Sapindaceae) has resulted in the isola-
tion of a new alkaloid, galloyl tyramine 1, an inhibitor
of the Pim2 kinase with IC50 values of 161 [8]. As a
part of our ongoing research in the total synthesis of
bio-active natural products [9], we now wish to report
the first total synthesis of galloyl tyramine 1.
The First Total Synthesis of Galloyl
Tyramine
Nisar Ullah
Chemistry Department, King Fahd University of Petroleum
and Minerals, Dhahran 31261, Saudi Arabia
Reprint requests to Professor Nisar Ullah.
Fax: + 966 3 860 4277. E-mail: nullah@kfupm.edu.sa
Results and Discussion
Z. Naturforsch. 2009, 64b, 464 – 466;
received December 17, 2008
Our synthetic strategy (Scheme 1) commenced with
the synthesis of perbenzylated gallic acid 4, which was
prepared by adopting a known procedure with some
modifications. Benzylation of methyl gallate 2 with
benzyl bromide in DMF [10], followed by hydrolysis
of the ester by LiOH to produce 4, was not only high-
yielding (96 %) but also no additional workup was nec-
essary as opposed to usage of KOH as a base [10]. The
coupling of acid 4 with N-t-Boc-tyramine 6 [11] using
dicyclohexylcarbodiimide yielded a complex mixture
of products with no trace of the desired carbamate 7.
In another attempt the acid 4 was transformed to the
corresponding acid chloride 5, which in turn was added
to a stirred solution of N-t-Boc-tyramine 6 in CH2Cl2
and Et3N at r. t. rendering the desired carbamate 7 in
70 % yield after column chromatography purification.
Hydrogenation of compound 7 generated the interme-
diate 8, which in turn was deprotected by the action of
trifluoroacetic acid in CH2Cl2 to produce the desired
galloyl tyramine 1 in 71 % yield (Scheme 1).
The first total synthesis of galloyl tyramine, an inhibitor
of Pim2 kinase was accomplished in an overall high-yield
reaction sequence.
Key words: Total Synthesis, Natural Product, Antitumor
Agent
Introduction
The Pim family of cytoplasmic serine/threonine ki-
nases comprises three proto-oncogenes, Pim1, Pim2,
and Pim3. With specificity towards phosphorylation
on serine/threonine residues, this distinct class of ki-
nases collectively contributes to the control of pro-
grammed cell death and cellular metabolism [1, 2].
There is more than 53 % identity in the amino-acid
level among the three family members with each hav-
ing a somewhat different pattern of tissue distribu-
tion [3]. Because these kinases phosphorylate some
of the same substrates, there appears to be a certain
level of redundancy in their function. Mice with a defi-
ciency for all Pim kinases display a significant reduc-
tion in body size and impaired growth factor signal-
ing in hematopoietic cells, suggesting that physiolo-
gically the Pim kinases are important in growth factor
signaling [4]. Deregulated Pim kinase expression has
been reported in a variety of myeloid and lymphoblas-
tic leukemias [5], in other cancers such as prostate can-
cer, B cell lymphoma, chronic lymphocytic leukemia,
acute myelogenous leukemia [6], and also its implica-
tion in Moloney murine leukemia virus-induced lym-
phomas [3, 7]. Thus, the discovery of Pim kinases in-
hibitors has a good potential to find applications in the
treatment of various diseases including cancer, inflam-
matory disorders, and ischemic diseases [6].
Conclusion
In conclusion we have accomplished the efficient
first total synthesis of galloyl tyramine 1, an inhibitor
of Pim2 kinase in an overall 47 % yield from 4 and 6.
Experimental Section
3,4,5-Tris(benzyloxy)benzoic acid (4)
Ester 3 (0.8 g, 1.76 mmol) was dissolved in a 1 : 2 : 1 mix-
ture of 16 mL of MeOH, THF and H2O, followed by the
addition of LiOH·H2O (0.22 g, 5.28 mmol), and the reaction
mixture was stirred for 12 h at r. t. The mixture was con-
centrated in vacuo to remove the organic solvents, 6 N HCl
(20 mL) was added, and the resulting white crystalline ma-
terial of 4 was filtered, washed with H2O (3 mL) and dried
under vacuum to get acid 4 as a white solid, whose physical
and spectral data were identical to the reported ones [10].
c
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Note
465
Scheme 1. Synthesis of galloyl tyramine (1).
tert-Butyl 4-[3,4,5-tri(benzyloxy)benzoyloxy]phenethyl-
carbamate (7)
ture was stirred at r. t. for 2 h, the solvents were evaporated,
and the brown oily material was resolved on a silica column
eluting with hexanes-ethyl acetate = 8 : 2 to affor◦d 0.26 g
(70 %) of 7 as an off-white solid. M. p. 94 – 95 C. – IR
(neat): ν = 3367, 2932, 1728, 1682, 1586, 1506, 1331, 1181,
To a solution of acid 4 (0.3 g, 0.68 mmol) in THF (10 mL)
was added SOCl2 (0.2 mL, 2.74 mmol), and the mixture was
stirred for 4 h at r. t. and evaporated to dryness to afford
the acid chloride 5. In another flask carbamate 6 (0.13 g,
0.57 mmol), was dissolved in CH2Cl2 (5 mL), and Et3N
(0.19 mL) was added, and the mixture was stirred for 15 min
at r. t., followed by the drop-by-drop addition of the acid
chloride 5, dissolved in 2 mL of CH2Cl2. The reaction mix-
1
1112, 951, 739 cm−1. – H NMR (500 MHz, CDCl3): δ =
1.44 (s, 9 H, COOC(CH3)3), 2.81 (t, J = 7.4 Hz, 2 H, 2-H),
3.38 (m, 2 H, 1-H), 5.15 (s, 6 H, CH2Ph), 7.11 (d, J = 8.2 Hz,
2 H, 5-H, 7-H), 7.27 – 7.23 (m, 4 H, aromatic H), 7.44 – 7.32
(m, 14 H, aromatic H), 7.52 (s, 2 H, 3ꢀ-H, 7ꢀ-H). – 13C NMR
(125.7 MHz, CDCl3): δ = 28.41 (COOC(CH3)3), 35.60
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466
Note
(C-2), 41.73 (C-1), 71.25 (CH2Ph), 75.15 (CH2Ph), 79.26 [D6]DMSO): δ = 1.44 (s, 9 H, COOC(CH3)3), 2.78 (t, J =
(COOC(CH3)3), 109.58 (C-3ꢀ, C-7ꢀ), 121.75 (C-5, C-7), 7.3 Hz, 2 H, 2-H), 3.21 (m, 2 H, 1-H), 6.97 (m, 1 H, NH
124.43 (C-2ꢀ), 127.56 (Carom), 128.0 (Carom), 128.10 (V), COOC(CH3)3), 7.15 (s, 2 H, 3ꢀ-H, 7ꢀ-H), 7.18 (d, J = 8.2 Hz,
128.21 (Carom), 128.54 (Carom), 129.80 (C-4, C-8), 136.52 2 H, 5-H, 7-H), 7.31 (d, J = 8.2 Hz, 2 H, 4-H, 8-H), 9.20
(Cq-aryl), 136.69 (Cq-aryl), 137.33 (C-3), 142.93 (C-5ꢀ), (s, 1 H, OH-5ꢀ), 9.47 (s, 2 H, OH-4ꢀ, OH-6ꢀ). – 13C NMR
149.50 (C-6), 152.63 (C-4ꢀ, C-6ꢀ), 155.88 (COOC(CH3)3), (125.7 MHz, [D6]DMSO): δ = 28.28 (COOC(CH3)3), 34.77
164.81 (C-1ꢀ). – C41H41NO7 (659.29): calcd. C 74.64, (C-2), 41.49 (C-1), 77.55 (COOC(CH3)3), 109.10 (C-3ꢀ,
H 6.26, N 2.12; found C 74.60, H 6.28, N 2.09.
C-7ꢀ), 118.33 (C-2ꢀ), 121.74 (C-5, C-7), 129.59 (C-4, C-8),
136.85 (C-3), 139.20 (C-5ꢀ), 145.74 (C-4ꢀ, C-6ꢀ), 149.14
(C-6), 155.55 (COOC(CH3)3), 164.68 (C-1ꢀ). – C20H23NO7
(389.15): calcd. C 61.69, H 5.96, N 3.60; found C 61.66,
H 5.99, N 3.56.
tert-Butyl 4-[3,4,5-tri(hydroxy)benzoyloxy]phenethyl-
carbamate (8)
To a solution of compound 7 (0.2 g, 0.30 mmol) in a
2 : 1 mixture of THF and MeOH (15 mL) was added 0.04 g
of Pd/C (10 %), and the reaction mixture was subjected to
hydrogenation in a Parr apparatus at 50 psi for 5 h. The
mixture was filtered through a pad of celite, and the fil-
trate was concentrated under vacuum and loaded on a silica
column, eluting with hexanes-ethyl acetate = 3 : 7 and then
changing to ethyl acetate (100 %) to afford 0.11 g (94 %)
of 8 as a white foam. – IR (neat): ν = 3382, 2966, 1701,
1685, 1318, 1190, 1164, 1033 cm−1. – 1H NMR (500 MHz,
Galloyl tyramine (1)
Compound 8 (0.06 g, 0.15 mmol) was dissolved in THF
(5 mL) followed by the addition of trifluoroacetic acid
(1 mL), and the mixture was stirred at r. t. for 8 h. The sol-
vents were evaporated under vacuum, and the brown thick
oily material was washed thoroughly with CH2Cl2 to pro-
duce 0.043 g (71 %) of 1. The spectral data of our synthetic
1 were identical to those of the natural material [8].
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