Novel synthesis of a 1,3,5-trioxazatriquinane skeleton using a nitrogen clamp

Article abstract of DOI:10.1021/ol8024988

(Chemical Equation Presente) An α-hydroxyaldehyde derived from naltrexone was converted to an oxazoline dimer with ammonium chloride and sodium acetate in MeOH under reflux. The resulting dimer was treated with dl-camphorsulfonic acid in CHCl3 to give the trimer. The method for trimer synthesis was also applied to general α-hydroxyaldehydes to afford trimers in good yield.

Full text of DOI:10.1021/ol8024988

ORGANIC
LETTERS
2009
Vol. 11, No. 3
539-542
Novel Synthesis of a
1,3,5-Trioxazatriquinane Skeleton Using
a Nitrogen Clamp
Hiroshi Nagase,*,† Akio Watanabe,† Masaya Harada,† Mayumi Nakajima,‡
Ko Hasebe,‡ Hidenori Mochizuki,‡ Kenji Yoza,§ and Hideaki Fujii†
School of Pharmacy, Kitasato UniVersity, 5-9-1 Shirokane, Minato-ku,
Tokyo 108-8641, Japan, Pharmaceutical Research Laboratries, Toray Industries, Inc.,
6-10-1, Tebiro, Kamakura, Kanagawa 248-8555, Japan, and BRUKER AXS K.K.,
AdVanced X-ray Solutions, 3-9-A Moriya-cho, Kanagawa-ku, Yokohama-shi,
Kanagawa 211-0022, Japan
nagaseh@pharm.kitasato-u.ac.jp
Received October 28, 2008
ABSTRACT
An r-hydroxyaldehyde derived from naltrexone was converted to an oxazoline dimer with ammonium chloride and sodium acetate in MeOH
under reflux. The resulting dimer was treated with dl-camphorsulfonic acid in CHCl3 to give the trimer. The method for trimer synthesis was
also applied to general r-hydroxyaldehydes to afford trimers in good yield.
Naltrexone 1 is a µ opioid receptor antagonist and widely
used for therapy of drug addiction. We have been interested
in design and synthesis of κ, δ, and ε opioid receptor selective
ligands from naltrexone 1 and have successfully synthesized
many selective κ, δ, and ε antagonists and agonists.1 We
also reported many new reactions using naltrexone as a
starting material.2 Recently, we have reported that twin drug
2 (Figure 1), which was also prepared from naltrexone 1,
showed ε receptor antagonist activity.3 In the course of the
† Kitasato University.
Figure 1. Structures of naltrexone 1, twin drug 2, and triplet drug
‡ Toray Industries, Inc.
3 (the 1,3,5-trioxazatriquinane skeleton was highlighted by red and
§ BRUKER AXS K.K.
blue colors).
(1) (a) Portoghese, P. S.; Sultana, M.; Nagase, H.; Takemori, A. E.
J. Med. Chem. 1988, 31, 281–282. (b) Portoghese, P. S.; Nagase, H.;
Lipkowski, A. W.; Larson, D. L.; Takemori, A. E. J. Med. Chem. 1988,
31, 836–841. (c) Portoghese, P. S.; Nagase, H.; Takemori, A. E. J. Med.
Chem. 1988, 31, 1344–1347. (d) Portoghese, P. S.; Nagase, H.; Maloney-
Huss, K. E.; Lin, C.-E.; Takemori, A. E. J. Med. Chem. 1991, 34, 1715–
1720. (e) Nagase, H.; Hayakawa, J.; Kawamura, K.; Kawai, K.; Takezawa,
Y.; Matsuura, H.; Tajima, C.; Endo, T. Chem. Pharm. Bull. 1998, 46, 366–
369. (f) Fujii, H.; Nagase, H. Curr. Med. Chem. 2006, 13, 1109–1118.
synthetic investigation of 2, we found that triplet drug 3 with
a 1,3,5-trioxazatriquinane skeleton (highlighted by red and
blue colors in Figure 1) was unexpectedly obtained. In this
molecule, nitrogen plays an important role in the formation
10.1021/ol8024988 CCC: $40.75
Published on Web 12/30/2008
2009 American Chemical Society

of the novel skeleton. Nitrogen is a trivalent atom which
serves to gather the three molecular units having a keto
moiety and to fix them in a precise and rigid fashion as a
trimer. Nitrogen acts in a manner analogous to a three-
pronged clamp, and we would like to term this phenomenon
as a “nitrogen clamp”. The nitrogen clamp may be expected
to apply the general synthesis of triplet drugs from various
ketones which would show unique pharmacological effects.
Herein, we report a novel synthetic method for triplet drugs
with a rigid 1,3,5-trioxazatriquinane skeleton using a nitrogen
clamp.
We have recently reported that acetal dimer 7, a precursor
of the twin drug 2, was obtained from a mixture of
R-hydroxyaldehyde 4, hemiacetal 5, and hemiacetal dimer
6 derived from naltrexone 1 in four steps.3 Examination of
the products of the synthesis of acetal dimer 7 revealed novel
trimer 3 with the 1,3,5-trioxazatriquinane skeleton in 10%
yield, concomitantly with acetal dimer 7 in 13% yield
(Scheme 1). At first, the nitrogen source was not clear, but
Figure 2. X-ray crystallography of trimer 3.
Scheme 1. Syntheses of Acetal Dimer 7 and Trimer 3
the reaction mechanism. When the mixture of compounds
4, 5, and 6 was treated with ammonium chloride and sodium
acetate in MeOH under reflux, oxazoline dimer 8a (46%)
and its isomer 8b (9%) were obtained (Scheme 2). Moreover,
Scheme 2. Synthesis of Trimer 3 via Dimer 8
after a precise search, we determined that the nitrogen was
derived from the solvent (saturated ammonia-CHCl3) which
was used in preparative TLC for separation of the objective
dimer 7. The structure of trimer 3 was determined by X-ray
crystallography (Figure 2). We were interested in the novel
structure of 3 and tried to improve the yield of 3 and clarify
acetal 9, which was a precursor of the mixture of compounds
4, 5, and 6, was hydrolyzed with 2 M HCl under reflux, and
the resulting mixture (without purification) was treated with
ammonium chloride and sodium acetate in MeOH under
reflux to afford a mixture of oxazoline 8a (45%) and its
isomer 8b (43%) (Scheme 2). Dimer 8b was treated with
dl-camphorsulfonic acid (CSA) in CHCl3 under reflux to give
a mixture of dimer 8a (30%) and trimer 3 (30%). On the
other hand, dimer 8a was converted to trimer 3 in 68% yield
under the same conditions (Scheme 2). These observations
supported the idea that dimer 8a may be the stable isomer
and 8b may be the unstable one, which could be converted
to trimer 3 via stable isomer 8a. Interestingly, X-ray analysis
(2) (a) Nagase, H.; Abe, A.; Portoghese, P. S. J. Org. Chem. 1989, 54,
4120–4125. (b) Fujii, H.; Mizusuna, A.; Tanimura, R.; Nagase, H.
Heterocycles 1997, 45, 2109–2112. (c) Fujii, H.; Hirano, N.; Uchiro, H.;
Kawamura, K.; Nagase, H. Chem. Pharm. Bull. 2004, 52, 747–750. (d)
Watanabe, A.; Kai, T.; Nagase, H. Org. Lett. 2006, 8, 523–526. (e) Osa,
Y.; Ida, Y.; Furuhata, K.; Nagase, H. Heterocycles 2006, 69, 271–282. (f)
Nagase, H.; Watanabe, A.; Nemoto, T.; Yamamoto, N.; Osa, Y.; Yoza, N.;
Kai, T. Tetrahedoron Lett. 2007, 48, 2547–2553.
(3) Fujii, H.; Watanabe, A.; Nemoto, T.; Narita, M.; Miyoshi, K.;
Nakamura, A.; Suzuki, T.; Nagase, H. Bioorg. Med. Chem. Lett. 2009, 19,
438-441.
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Org. Lett., Vol. 11, No. 3, 2009

Table 1. General Synthesis of Trimers
showed that the absolute configuration of the three newly
formed asymmetric centers of the 1,3,5-trioxazatriquinane
moiety in trimer 3 were the all-S configurations. The selective
formation of the asymmetric centers may be attributed to
the above considerations, a series of reactions from acetal 9
to trimer 3 were performed without purification to afford 3
in 79% yield. Oxycodone 10 also afforded trimer 11 in 6%
total yield (Scheme 3).
Next, we examined the application of this reaction to
model compounds to confirm the generality of the reaction
(Table 1). N-Benzylpiperidone was converted to trimer 14
in 18% total yield. Acetophenone was converted to a mixture
of trimers 16a, 16b, and 16c in 35% total yield. Thioacetals
17a and 17b, obtained from 4-phenyl cyclohexanone, were
converted to trimer 18a (35%) and 18b (13%), respectively.4
We also tried to apply this reaction to synthesis of a
nonsymmetric trimer (Scheme 4). The dimer 19, prepared
from 4-phenylcyclohexanone, was reacted with R-hydroxy-
aldehyde 20 (CSA/CHCl3, reflux) to afford nonsymmetrical
trimer 21 in 91% yield. The dimer 19 was also converted to
nonsymmetric trimer 22 with the glycolaldehyde dimer
(CSA/CHCl3, rt) in 98% yield. Furthermore, dimers 8a and
8b, obtained from a mixture of 4, 5, and 6, were reacted
with 23 (derived from haloperidol), 24, and glycolaldehyde
Scheme 3. Synthesis of the N-Methyl Trimer
asymmetric induction by the natural naltrexone skeleton. We
also assigned configuration of the * position in dimer 8a
and 8b as S and R (Scheme 2), respectively, by 2D NMR
spectroscopy. Eventually, R configuration isomer 8b would
be the kinetically controlled product, and S isomer 8a would
be the thermodynamically controlled one. On the basis of
(4) Determination of the stereochemistry of trimers 14, 16, and 18 was
described in the Supporting Information.
Org. Lett., Vol. 11, No. 3, 2009
541

applied to the synthesis of not only symmetrical trimers but
also nonsymmetrical ones. Recent studies have reported that
G-protein-coupled receptors (GPCRs) exist as dimers, which
may be present as homo- or heterodimers/oligomers. Al-
though the existence of GPCR dimers/oligomers was pre-
dicted from early pharmacological and biochemical studies,5
further evaluations of this phenomenon were impeded by
the lack of appropriate reagents.6 Twin drugs combining two
structural components into a single molecule have been
described in numerous domains of medicinal chemistry.
Symmetrical twin drugs can simultaneously fit to the
symmetrical binding sites of the protein complex to afford
increased activity. Nonsymmetrical twin drugs, in contrast,
may bind to the individual relevant binding sites to give dual
action. However, twin drugs can only play one role, either
an increase of activity or a dual action. On the other hand,
nonsymmetrical triplet drugs which have two of the same
moieties and one different substituent may exhibit both
increased pharmacological action and dual action because
the two identical portions could bind the same receptor sites
simultaneously while the third portion could bind a different
receptor site or enzyme. Moreover, a symmetrical triplet drug
12 showed 20 times stronger analgesic activity than mono-
meric compound morphine, suggesting that symmetrical
triplet drugs would indicate extremely potent activities.
Therefore, the thus obtained trimers with the rigid 1,3,5-
trioxazatriquinane skeleton using a nitrogen clamp may be
a very useful tool for investigation of oligomeric receptors
and enzymes.
Scheme 4. Syntheses of Nonsymmetric Trimers
Acknowledgment. We acknowledge the Institute of
Instrumental Analysis of Kitasato University, School of
Pharmacy, for its facilities. We also acknowledge the Uehara
Memorial Foundation for financial support.
dimer to give nonsymmetric trimer 25, 26, and 27 in yields
of 23%, 50%, and 75%, respectively. The symmetrical trimer
12, obtained from oxycodone 10, showed potent analgesic
action in the acetic acid writhing assay (ED50 ) 0.037 mg/
kg) that was about 20 times more potent than that of
morphine (ED50 ) 0.6 mg/kg). The strong analgesic potency
may derive from the binding with oligomeric receptor sites.5
In conclusion, we have established the first general
synthetic method for the trimer with a 1,3,5-trioxaza-
triquinane skeleton using a nitrogen clamp which could be
Supporting Information Available: Experimental pro-
cedures, full characterization of compounds, 1H NMR spectra
and CIF file of X-ray crystallography of compound 3, 2D
1
NMR spectra of compounds 8a, 8b, and H NMR spectra
of compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL8024988
(5) (a) Rios, C. D.; Joran, B. A.; Gomes, I.; Devi, L. A. Pharmacol.
Ther. 2001, 92, 71–87. (b) Levac, B. A. R.; O’Dowd, B. F.; George, S. R.
Curr. Opin. Pharmacol. 2002, 2, 76–81.
(6) Contreras, J.-M.; Bourguignon, J.-J. In The practice of Medicinal
Chemistry, 2nd ed.; Wermuth, C. G., Ed.; Academic press: London, 2003;
pp 251-273.
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