The synthesis of substituted (4S)-4-(hydroxymethyl)imidazolidin-2-ones as novel protein kinase C modulators

Article abstract of DOI:10.1016/S0040-4039(00)01561-6

The total synthesis of substituted (4S)-4-(hydroxymethyl)imidazolidin-2-ones from D-serine methyl ester is described. The key step in the synthesis is a reductive amination reaction which is brought about using titanium(IV) isopropoxide and sodium cyanoborohydride, followed by the cyclization to urea using triphosgene after deprotection. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01561-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8711–8715
The synthesis of substituted
(4S)-4-(hydroxymethyl)imidazolidin-2-ones as novel protein
kinase C modulators
Lianyun Zhao, Lixin Qiao, Suo-Bao Rong and Alan P. Kozikowski*
Drug Discovery Program, Department of Neurology, Georgetown University Medical Center, 3900 Reservoir Road,
NW, Washington, DC 20007-2197, USA
Received 23 July 2000; revised 31 August 2000; accepted 2 September 2000
Abstract
The total synthesis of substituted (4S)-4-(hydroxymethyl)imidazolidin-2-ones from D-serine methyl
ester is described. The key step in the synthesis is a reductive amination reaction which is brought about
using titanium(IV) isopropoxide and sodium cyanoborohydride, followed by the cyclization to urea using
triphosgene after deprotection. © 2000 Elsevier Science Ltd. All rights reserved.
Protein kinase C (PKC) is a ubiquitous diacylglycerol (DAG) activated signal transducing
enzyme system that plays important roles in cell growth, differentiation, apoptosis, ion channel
modulation, neurotransmitter release, neuronal plasticity, and tumor promotion.1 Compounds
that selectively modulate certain PKC isozymes cannot only serve as important tools in the
elucidation of their physiological roles, but also hold promise in the development of novel
therapeutics for the treatment of human diseases, such as cancer and Alzheimer’s dementia.2
However, few isozyme-selective activators have been reported, although several isozyme-selective
inhibitors have been developed in the past few years.3 Various natural products like the
teleocidins, as well as analogs of indolactam V (ILV) bearing a hydrocarbon appendage at the
7-position of the indole ring have been shown to function as DAG mimics, and to activate PKC
at low concentrations.4 The synthesis and structure–activity relationships of ILV and its analogs
still continue to fascinate both synthetic and medicinal chemists (Fig. 1).5
With the aid of molecular modeling based on the X-ray crystal structure of the CRD2 domain
of PKCd in complex with phorbol 13-acetate,6 our group has reported the design, synthesis, and
biological activities of certain pyrrolidone derivatives 1 as a class of novel PKC modulators.7 In
further pursuit of these five-membered ring analogs as PKC activators, we focussed on the
isopropyl group in template 1. From our molecular modeling studies (Fig. 2),8 we found that
* Corresponding author. Tel: (202)-687-0686; fax: (202)-687-5065; e-mail: kozikowa@giccs.georgetown.edu
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01561-6

8712
Figure 1.
there is still some space existing between the isopropyl group of compound 1 and the PKC
residue Leu254. When C-3% in these pyrrolidone analogs is replaced by a nitrogen atom, an
improved interaction between the isopropyl group of the ‘flattened’ imidazolidinone 3 and
Leu254 is observed, suggesting that a possibly improved PKC binding affinity might result. The
hydrogen bonding network and hydrophobic interactions between the aromatic ring and Pro241
remain intact for these new analogs. A further distinct advantage of the urea analogs derives
from the removal of one chiral center, which simplifies their chemical synthesis. Moreover, these
analogs provide us with the opportunity to maximize interaction with the cell membrane in two
ways, this being that an appropriate hydrocarbon appendage can be introduced at either a site
on the aromatic ring (as was done for 1) or at N-1. A recent publication has shown that
2-alkylated benzolactams 2 with a C8–C14 hydrocarbon appendage achieve a PKC binding
affinity comparable to that of phorbol 12,13-dibutyrate (PDBu).9 Thus, in analogy to this work,
we postulated that the introduction of suitable hydrocarbon residues to the N-1 might offer a
means of further improving upon PKC affinity, as well as providing means for achieving
isozyme selectivity. Herein, we disclose chemical routes to these (4S)-4-(hydroxy-
methyl)imidazolidin-2-ones 3.
Figure 2. Molecular modeling studies for 3b. Left: overlay of compounds 1 and 3b. Right: the overall features of the
binding model for compound 3b in complex with PKCd CRD2
Using similar procedures as reported earlier,10,11 the Cbz-protected aldehyde 4 was obtained
starting from D-serine methyl ester (Scheme 1). Treatment of the amino aldehyde 4 with
p-bromophenylmagnesium bromide at −78°C gave the alcohol 5 as a mixture of diastereoiso-
mers. Perruthenate-catalyzed oxidation of the resulting secondary alcohol furnished the ketone
6.12 The side chain on the phenyl ring was introduced by coupling the bromide with 1-decyne

8713
under the catalysis of PdCl2(PPh3)2 and CuI. The resulting ketone 7 was then converted into an
imine with isopropylamine in the presence of titanium(IV) isopropoxide as catalyst,13 and the
derived imine was converted to amine by reduction with sodium cyanoborohydride. The
corresponding amines 8 and 9 were obtained in a ratio of 9:7. These two isomers can be
separated by careful flash column chromatography. After deprotection by transketalization with
ethanedithiol in the presence of BF3·Et2O in CH2Cl2 at reflux, the resulting products were
treated directly with triphosgene in 1,4-dioxane/water in the presence of Na2CO3 to yield the
desired compounds 3a and 3b in 28% and 35% yield, respectively.14
Scheme 1. Reagents and conditions: (a) Et3N, CbzCl, CHCl3, rt, 24 h, 97%; (b) PPTS, 2,2-dimethoxypropane, toluene,
70°C, overnight, then reflux, 92%; (c) DIBAL-H, dry toluene, −78°C, 2 h, 87%; (d) p-BrPhMgBr, THF, −78°C, 82%;
,
(e) NMO, 4 A MS, TPAP, CH2Cl2/CH3CN, rt, overnight, 85%; (f) PdCl2(PPh3)2, CuI, 1-decyne, Et3N/DMF, 80°C,
6 h, 70%; (g) (i) isopropylamine, Ti(O-iPr)4, rt, 6 h; (ii) NaCNBH3, EtOH, rt, 16 h, 8: 48%, 9: 37%; (h) (i) BF3·Et2O,
1,2-ethanedithiol, dry CH2Cl2, reflux, 6 h; (ii) triphosgene, dioxane/H2O, Na2CO3, rt, 1 h, 3a: 28%, 3b: 35%
The absolute configuration of the stereocenters present in 3a and 3b were assigned based upon
1
an analysis of their H NMR spectra and in accordance with their derivation from
D
-serine. In
the proton NMR spectrum of 3a, the resonance corresponding to the benzylic proton Ha was
observed as a doublet with a coupling constant of 9.0 Hz, indicating a cis relationship to Hb.
1
Similarly, the H NMR signal corresponding to the benzylic proton of 3b was observed as a
doublet with a coupling constant of 5.4 Hz, indicating a trans substitution pattern.
In the same manner as described above, aldehyde 4 was treated with either phenylmagnesium
bromide or naphthylmagnesium bromide to provide the corresponding alcohol 10 (Scheme 2),
which was converted to ketone 11 by a perruthenate-catalyzed oxidation reaction. The ketone 11
was reacted in turn with isopropylamine or dodecylamine in the presence of titanium(IV)
isopropoxide, followed by the reduction with sodium cyanoborohydride to give a mixture of the
amines 12 and 13 in a ratio of about 1:1. Finally, the protecting group of each of the amines 12
and 13 was removed by a hydrogenation reaction in the presence of 20% Pd(OH)2/C as catalyst,

8714
,
Scheme 2. Reagents and conditions: (a) ArMgBr, THF, −78°C; (b) NMO, 4 A MS, TPAP, CH2Cl2/CH3CN, rt,
overnight; (c) (i) RNH2, Ti(O-i-Pr)4, rt, 6 h; (ii) NaCNBH3, EtOH, rt, 16 h; (d) (i) H2, 20% Pd(OH)2/C, MeOH, 1
atm, rt, 30 min; (ii) triphosgene, dioxane/H2O, NaHCO3, rt, 1 h
followed by treatment with triphosgene and NaHCO3 to give the desired cyclic ureas 3c–3g15 in
a yield of 25–40% from 12 and 13, respectively.
In summary, the present article outlines an efficient means for constructing the urea analogs
of our previously disclosed pyrrolidone-based PKC activators. As some of these pyrrolidones
have been shown to possess useful biological activity in blocking tumor growth in vivo, these
ureas will also be of interest to study for their PKC activity. The urea analogs are particularly
valuable from the standpoint of their greater ease of synthesis, which derives from the deletion
of one chiral center. A comprehensive report on the biological activity of these ureas will be
published in due course.
Acknowledgements
This work was supported by the Department of Defense (DMAD 17-93-V-3018) and NIH
grant CA79601.
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1
14. Compound 3a: H NMR (CDCl3, 300 MHz) l 7.38 (d, J=7.8 Hz, 2H), 7.26 (d, J=7.8 Hz, 2H), 4.79 (d, J=9.0
Hz, 1H), 4.75 (br s, 1H), 4.00 (m, 1H), 3.87 (m, 1H), 3.19 (m, 2H), 2.41 (t, J=7.2 Hz, 2H), 1.59 (m, 2H), 1.45
(m, 2H), 1.30 (br s, 8H), 1.25 (d, J=6.6 Hz, 3H), 0.90 (m, 6H). 13C NMR (CDCl3) l 14.09, 19.37, 20.33, 20.82,
22.63, 28.67, 28.91, 29.09, 29.17, 31.81, 45.35, 56.40, 59.97, 63.27, 79.96, 91.36, 124.20, 127.56, 131.61, 136.64,
1
162.48. Compound 3b: H NMR (CDCl3, 300 MHz) l 7.38 (d, J=8.1 Hz, 2H), 2.28 (d, J=8.1 Hz, 2H), 5.61 (s,
1H), 4.43 (d, J=5.4 Hz, 1H), 3.89 (m, 1H), 3.67 (m, 1H), 3.53 (m, 3H), 2.40 (t, J=7.2 Hz, 2H), 1.60 (m, 2H),
1.44 (m, 2H), 1.29 (br s, 8H), 1.17 (d, J=6.9 Hz, 3H), 0.86 (m, 6H). 13C NMR (CDCl3) l 14.10, 19.39, 19.65,
21.29, 22.65, 28.69, 28.92, 29.10, 29.18, 31.83, 45.35, 60.08, 61.02, 63.45, 80.00, 91.21, 124.12, 126.91, 131.99,
141.31, 162.01.
1
15. Compound 3c: H NMR (CDCl3, 300 MHz) l 7.38 (m, 3H), 7.22 (dd, J=2.1, 7.8 Hz, 2H), 5.44 (s, 1H), 4.83 (d,
J=9.0 Hz, 1H), 4.02 (m, 1H), 3.53 (m, 1H), 3.16 (m, 2H), 2.64 (m, 2H), 1.39 (t, J=6.9 Hz, 2H), 1.21 (m, 20H),
0.88 (t, J=6.9 Hz, 3H). Compound 3d: 1H NMR (CDCl3, 300 MHz) l 7.91 (m, 3H), 7.51 (m, 4H), 5.74 (d,
J=9.3 Hz, 1H), 5.25 (s, 1H), 4.23 (dt, J=4.2 Hz(d), 9.3 Hz(t), 1H), 3.66 (m, 1H), 3.12 (m, 1H), 2.92 (m, 1H),
1
2.75 (m, 1H), 1.78 (br s, 1H), 1.43 (m, 2H), 1.20 (m, 20H), 0.87 (t, J=6.9 Hz, 3H). Compound 3e: H NMR
(CDCl3, 300 MHz) l 7.37 (m, 5H), 5.58 (s, 1H), 4.46 (d, J=5.7 Hz, 1H), 3.90 (m, 1H), 3.69 (m, 1H), 3.56 (m,
1
3H), 1.20 (d, J=6.6 Hz, 3H), 0.86 (d, J=6.9 Hz, 3H). Compound 3f: H NMR (CDCl3, 300 MHz) l 7.36 (m,
5H), 5.06 (s, 1H), 4.46 (d, J=6.0 Hz, 1H), 3.72 (m, 1H), 3.59 (m, 2H), 3.41 (m, 1H), 2.65 (m, 2H), 1.36 (m, 2H),
1.22 (m, 20H), 0.88 (t, J=6.9 Hz, 3H). Compound 3g: 1H NMR (CDCl3, 300 MHz) l 7.90 (m, 3H), 7.54 (m, 4H),
5.54 (d, J=5.1 Hz, 1H), 4.70 (s, 1H), 3.50–3.90 (m, 5H), 2.73 (m, 1H), 1.42 (m, 2H), 1.90 (m, 20H), 0.87 (t, J=6.9
Hz, 3H).
.