A double decarboxylation reaction of an oxazolidinone and carboxylic acid: Its application to the synthesis of a new opioid lead compound

Article abstract of DOI:10.1021/jo9025463

(Chemical Equation Presented) Treatment of oxazolidinone carboxylic acid 6 with potassium carbonate gave olefin 7 by a double decarboxylation reaction. The reaction was proposed to proceed via decarboxylation followed by E1cB-like mechanism. 15,16-Nornaltrexone derivative 17 prepared from double decarboxylation product 7 showed strong affinity for the μ opioid receptor, indicating it to be a new opioid lead compound.

Full text of DOI:10.1021/jo9025463

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been proposed as another opioid receptor type, and extensive
A Double Decarboxylation Reaction of an
Oxazolidinone and Carboxylic Acid: Its Application
to the Synthesis of a New Opioid Lead Compound
pharmacological data support its existence.2 To obtain ideal
analgesics without addiction and without other side effects
derivedfromtheμ receptor, wehave synthesized various kinds
of naltrexone derivatives and have reported selective agonists
for δ, κ, and putative ε receptor.3-5 Moreover, we have also
reported many new reactions using naltrexone derivatives.6
Recently, we reported the 16-17 bond cleavage reaction of
the naltrexone derivative 1 to afford oxazolidinone derivative
2 (Scheme 1).6f This cleavage reaction is the first D ring-
opening reaction in the 4,5-epoxymorphinan skeleton and
prompted us to reinvestigate an opioid receptor-ligand bind-
ing model, the Beckett-Casy model,7 using 4,5-epoxymor-
phinan derivatives cleaved in their D rings.8 In the course of
the investigation, we found a novel double decarboxylation
reaction, and one of the resulting derivatives showed stronger
affinity for the μ receptor than did the classical and clinically
used μ agonist morphine. Herein, we describe a novel double
decarboxylation reaction and its application to synthesis of
opioid derivatives with a novel skeleton.
Hideaki Fujii,† Satomi Imaide,† Akio Watanabe,†
Kenji Yoza,‡ Mayumi Nakajima,§ Kaoru Nakao,§
Hidenori Mochizuki,§ Noriko Sato,† Toru Nemoto,† and
Hiroshi Nagase*,†
†School of Pharmacy, Kitasato University, 5-9-1, Shirokane,
Minato-ku, Tokyo 108-8641, Japan, ‡Advanced X-ray
Solutions, BRUKER AXS K.K., 3-9-A, Moriya-cho,
Kanagawa-ku, Yokohama-shi, Kanagawa 211-0022, Japan,
and §Pharmaceutical Research Laboratories,
Toray Industries, Inc., 6-10-1, Tebiro, Kamakura,
Kanagawa 248-8555, Japan
nagaseh@pharm.kitasato-u.ac.jp
Received December 4, 2009
SCHEME 1. C16-N17 Cleavage Reaction
Naltrexone acetal 1 was treated with 1-chloroethyl chloro-
formate (ACE-Cl) in the presence of potassium carbonate in
1,1,2,2-tetrachloroethane (TCE) to give oxazolidinone chlo-
ride 2 (Scheme 1),6f followed by treatment with sodium iodide
to afford iodide 3 in 94%. Ozonolysis of compound 4,
Treatment of oxazolidinone carboxylic acid 6 with po-
tassium carbonate gave olefin 7 by a double decarboxyla-
tion reaction. The reaction was proposed to proceed via
decarboxylation followed by E1cB-like mechanism.
15,16-Nornaltrexone derivative 17 prepared from double
decarboxylation product 7 showed strong affinity for the
μ opioid receptor, indicating it to be a new opioid lead
compound.
(4) δ agonists: (a) Nagase, H.; Kawai, K.; Hayakawa, J.; Wakita, H.;
Mizusuna, A.; Matsuura, H.; Tajima, C.; Takezawa, Y.; Endoh, T. Chem.
Pharm. Bull. 1998, 46, 1695. (b) Nagase, H.; Yajima, Y.; Fujii, H.; Kawa-
mura, K.; Narita, M.; Kamei, J.; Suzuki, T. Life Sci. 2001, 68, 2227. (c)
Nagase, H.; Osa, Y.; Nemoto, T.; Fujii, H.; Imai, M.; Nakamura, T.;
Kanemasa, T.; Kato, A.; Gouda, H.; Hirono, S. Bioorg. Med. Chem. Lett.
2009, 19, 2792.
(5) A putative ε agonist: Fujii, H.; Narita, M.; Mizoguchi, H.; Murachi,
M.; Tanaka, T.; Kawai, K.; Tseng, L. F.; Nagase, H. Bioorg. Med. Chem.
2004, 12, 4133.
Three types of opioid receptors (μ, δ, κ) are now well-
established not only by pharmacological studies but also by
molecular biological studies.1 The μ receptor type is believed
to be linked to narcotic addiction, and therefore, δ and κ types
are promising drug targets for analgesics without addiction. A
putative ε receptor, which has not yet been cloned, has also
(6) (a) Fujii, H.; Hirano, N.; Uchiro, H.; Kawamura, K.; Nagase, H.
Chem. Pharm. Bull. 2004, 52, 747. (b) Watanabe, A.; Kai, T.; Nagase, H. Org.
Lett. 2006, 8, 523. (c) Osa, Y.; Ida, Y.; Furuhata, K.; Nagase, H. Heterocycles
2006, 69, 271. (d) Nagase, H.; Watanabe, A.; Nemoto, T.; Yamamoto, N.;
Osa, Y.; Sato, N.; Yoza, K.; Kai, T. Tetrahedron Lett. 2007, 48, 2547. (e)
Nemoto, T.; Fujii, H.; Sato, N.; Nagase, H. Tetrahedron Lett. 2007, 48, 7413.
(f) Fujii, H.; Imaide, S.; Watanabe, A.; Nemoto, T.; Nagase, H. Tetrahedron
Lett. 2008, 49, 6293. (g) Nagase, H.; Watanabe, A.; Harada, M.; Nakajima,
M.; Hasebe, K.; Mochizuki, H.; Yoza, K.; Fujii, H. Org. Lett. 2009, 11, 539.
(h) Fujii, H.; Ogawa, R.; Ohata, K.; Nemoto, T.; Nakajima, M.; Hasebe, K.;
Mochizuki, H.; Nagase, H. Bioorg. Med. Chem. 2009, 17, 5983. (i) Fujii, H.;
Watanabe, A.; Nemoto, T.; Narita, M.; Miyoshi, K.; Nakamura, A.; Suzuki,
T.; Nagase, H. Bioorg. Med. Chem. Lett. 2009, 19, 438.
(7) (a) Beckett, A. H.; Casy, A. F. J. Pharm. Pharmacol. 1956, 6, 986. (b)
Beckett, A. H. J. Pharm. Pharmacol. 1956, 8, 848. (c) Casy, A. F.; Parfitt, R. T.
In Opioid Analgesics, Chemistry and Receptors; Plenum Press: New York, 1986;
pp 473-475.
(8) Imaide, S.; Fujii, H.; Watanabe, A.; Nemoto, T.; Nakajima, M.;
Nakao, K.; Mochizuki, H.; Nagase, H. Bioorg. Med. Chem. Lett. DOI
10.1016/j.bmcl.2009.12.039.
(1) Dhawan, B. N.; Cesselin, F.; Reisine, T.; Bradley, P. B.; Portoghese, P.
S.; Hamon, M. Pharmacol. Rev. 1996, 48, 567.
(2) Fujii, H.; Nagase, H. Curr. Med. Chem. 2006, 13, 1109 and references
therein.
(3) κ agonists: (a) Kawai, K.; Hayakawa, J.; Miyamoto, T.; Imamura, Y.;
Yamane, S.; Wakita, H.; Fujii, H.; Kawamura, K.; Matsuura, H.; Izumi-
moto, N.; Kobayashi, R.; Endo, T.; Nagase, H. Bioorg. Med. Chem. 2008, 16,
9188. (b) Nemoto, T.; Fujii, H.; Narita, M.; Miyoshi, K.; Nakamura, A.;
Suzuki, T.; Nagase, H. Bioorg. Med. Chem. Lett. 2008, 18, 6398. (c) Nagase,
H.; Watanabe, A.; Nemoto, T.; Yamaotsu, N.; Hayashida, K.; Nakajima,
M.; Hasebe, K.; Nakao, K.; Mochizuki, H.; Hirono, S.; Fujii, H. Bioorg.
Med. Chem. Lett. 2010, 20, 121.
DOI: 10.1021/jo9025463
r
Published on Web 01/13/2010
J. Org. Chem. 2010, 75, 995–998 995
2010 American Chemical Society

Fujii et al.
JOCNote
SCHEME 2. Elimination of the C15, C16 Moiety
SCHEME 3. Proposed Decarboxylation Mechanism of 6 via
Four-Membered Ring Intermediate A
SCHEME 4. Decarboxylation of Oxazolidinone 8
prepared from iodide 3 by an elimination reaction, gave al-
dehyde 5. The resulting aldehyde 5 was oxidized with sodium
chlorite (Pinnick oxidation)9 to afford carboxylic acid 6.
When the acid 6 was treated with potassium carbonate in
DMF, surprisingly, two carbon dioxide units (carboxyl group
and oxazolidinone unit) were simultaneously eliminated to
give olefin 7 in 93% yield (Scheme 2). The structure of com-
pound 7 was determined by X-ray crystallography.
The mechanism of the double decarboxylation reaction of
6 was assumed to proceed via four-membered ring inter-
mediate (β-lactone) A (Scheme 3).10-12 However, the treat-
ment of compound 8, which lacks a carboxyl group,
with potassium carbonate in methanol and water also
afforded the same decarboxylated compound 7 in 87% yield
(Scheme 4), while the same treatment in DMF furnished the
recovery of compound 8. This result may suggest an E2 or
E1cB elimination mechanism13,14 rather than a mechanism
that proceeds via a β-lactone. Although the E2 elimination
usually proceeds via an antiperiplanar transition state, the
C-O bond of the oxazolidinone ring and the carboxyl group
in 6, and the hydrogen in 8, respectively, lie in a synclinal
conformation, suggesting that the elimination reaction
would not likely occur via an E2 fashion.15,16 Therefore,
the double decarboxylation reaction would proceed by E1cB
mechanism, in which a carbanion B, arising from the first
decarboxylation of compound 6 or the deprotonation in
compound 8 by potassium carbonate, might be stabilized by
the phenyl ring and/or the carbonyl group in the oxazolidi-
none ring (Figure 1).
(9) Bal, B. S.; Childers, W. E. Jr.; Pinnick, H. W. Tetrahedron 1981, 37,
2091.
(10) Hara, S.; Taguchi, H.; Yamamoto, H.; Nozaki, H. Tetrahedron Lett.
1975, 16, 1545.
The decarboxylation of oxazolidinones 6 and 8 is see-
mingly similar to removal of the well-known amino protec-
tive group, the Fmoc group. Fmoc deprotection occurs
(11) The thermal decarboxylation of a β-lactone has been widely used for
preparation of an olefin. (a) Pommier, A.; Pons, J.-M. Synthesis 1993, 441.
(b) Rayner, C. M. In Comprehensive Organic Functional Group Transforma-
tions; Katritzky, A. R., Meth-Cohn, O., Rees, C. W., Eds.; Pergamon Press:
Oxford, 1995; Vol. 1, pp 673-718.
(12) Recent examples of the thermal decarboxylation of β-lactones: (a)
(14) Another possible mechanism is discussed in the Supporting Informa-
tion.
€
Braun, N. A.; Meier, M.; Schmaus, G.; Holscher, B.; Pickenhagen, W. Helv.
Chim. Acta 2003, 86, 2698. (b) Merlic, C. A.; Doroh, B. C. J. Org. Chem.
2003, 68, 6056. (c) Buckle, M. J. C.; Fleming, I.; Gil, S.; Pang, K. L. C. Org.
Biomol. Chem. 2004, 2, 749. (d) Shindo, M.; Matsumoto, K.; Shishido, K.
Chem. Commun. 2005, 2477. (e) Shindo, M.; Matsumoto, K.; Shishido, K.
Tetrahedron 2007, 63, 4271.
(15) Some examples of syn elimination have been reported in molecules in
which β-hydrogen and leaving group could not achieve an antiperiplanar
conformation. Smith, M. B.; March, J. In March’s Advanced Organic
Chemistry; 6th ed.; John Wiley & Sons: New York, 2007; pp 1482-1483
and references therein.
(13) Olefins have been prepared by elimination reaction in which oxazo-
lidinone functioned as a leaving group. (a) Danishefsky, S. J.; Panek, J. S. J.
Am. Chem. Soc. 1987, 109, 917. (b) Gates, K. S.; Silverman, R. B. J. Am.
Chem. Soc. 1989, 111, 8891. (c) Padwa, A.; Brodney, M. A.; Lynch, S. M.;
Rashatasakhon, P.; Wang, Q.; Zhang, H. J. Org. Chem. 2004, 69, 3735.
(16) In cyclic systems, the extent of anti and syn elimination depends on
ring size. Cyclohexyl systems have a very strong preference for anti elimina-
tion. (a) Carey, F. A.; Sundberg, R. J. In Advanced Organic Chemistry, Part A:
Structure and Mechanisms; 5th ed.; Springer: New York, 2007; p 559. (b) See
also ref 15.
996 J. Org. Chem. Vol. 75, No. 3, 2010

Fujii et al.
JOCNote
SCHEME 7. Hydrolysis of 9a0-Acetate 10 and 9a0-Carbamate 11
FIGURE 1. Possible effect of the carbonyl group in the oxazolidi-
none ring on stabilizing carbanion B.
SCHEME 5. Elimination Reaction of Compound 9
SCHEME 8. Removal of the Troc Protective Group and Mi-
gration of the Acetyl Group
SCHEME 6. Proposed Decarboxylation Mechanism of 9 via
Oxazolidinone 8
washydrolyzed underbasicconditions togive onlycompound
12 (Scheme 7). Finally, treatment of compound 9 with zinc in
acetic acid afforded acetamide 14 by migration of the acetyl
group (Scheme 8), which was never converted into olefin 7
with basic treatment. Taken together, these results strongly
suggest that compound 7 would be obtained via oxazolidi-
none 8 (path A) but not by path B (Scheme 6), indicating that
the oxazolidinone structure may play an important role in the
second decarboxylation reaction. Moreover, treatment of
acyclic carbamate 11 with potassium carbonate gave only
compound 12 by hydrolysis. This result supports the impor-
tance of the cyclic carbamate, oxazolidinone structure in the
second decarboxylation reaction.
Compound 7 has a novel structure that loses the D ring (see
Scheme 1) from its 4,5-epoxymorphinan skeleton. Therefore,
we next evaluated the affinity of compound 17, derived from 7,
for the opioid receptor. Compound 17 was prepared from 7, as
shown in Scheme 9. The secondary amino group in olefin 7 was
protected by a Cbz group followed by oxidation with mCPBA
and subsequent hydrogenation of 15 to provide compound 16.
The stereochemistries of compounds 15 and 16 were deter-
mined by 2D NMR experiments of their analogues.18 Com-
pound 16 was converted into compound 12 by reductive
alkylation, followed by acidic deprotection of the acetal and
subsequent demethylation with BBr3 to give the objective
compound 17. In the competitive binding assay,6h compound
17 showed stronger binding affinity (Ki = 1.17 nM) for the
μ receptor than that of morphine (Ki = 1.98 nM), thus indi-
cating that it could be a new lead compound useful for
designing receptor-type-selective opioid ligands.
through cleavage by a weak base such as an amine via
elimination and simultaneous decarboxylation.17
Compound 7 was also obtained by the treatment of 9a0-
acetyl-N-trichloroethoxycarbonyl derivative 9 with potas-
sium carbonate in methanol and water at 80 °C in 80% yield
(Scheme 5). Compound 7 was proposed to be produced by
decarboxylation of 8 (Scheme 6, path A) because the treat-
ment of compound 9 with potassium carbonate at room
temperature gave oxazolidinone 8 (Scheme 5), which was
converted into compound 7 by the same treatment at 80 °C
(Scheme 4). Another possible route was via respective hydro-
lysis of carbamate and elimination of acetate (Scheme 6, path
B). However, path B can be ruled out by the following results.
First, hydrolysis of the carbamate required harsher reaction
conditions and longer reaction time.6f Second, 9a0-acetate 10
(17) Clayden, J.; Greeves, N.; Warren, S.; Wother, P. In Organic Chem-
istry; Oxford University Press: New York, 2001; pp 496-497.
(18) Determination of the stereochemistries of compounds 15 and 16 is
described in the Supporting Information.
J. Org. Chem. Vol. 75, No. 3, 2010 997

Fujii et al.
JOCNote
SCHEME 9. Synthesis of 15,16-Nornaltrexone Derivative 17
ethyl acetate solution to give compound 7 (3.2 g, 93%) as
white needles.
Decarboxylation Reaction of Compound 8. Under argon, to
a solution of compound 8 (11 mg, 0.028 mmol) in methanol
(1 mL) was added saturated potassium carbonate solution
(1 mL), and the mixture was stirred at 80 °C for 19 h. The
reaction mixture was poured into distillated water and extracted
with chloroform, and then dried over anhydrous sodium sulfate.
After removing the solvent under reduced pressure, the residue
was purified by silica gel column chromatography (CHCl3/
MeOH = 100/0 to 100/3) to give compound 7 (8.5 mg, 87%)
as white needles.
(3a0R,90R,E)-N-(Cyclopropylmethyl)-50-methoxy-10,3a0,80,90-
tetrahydro-20H-spiro[1,3-dioxolane-2,30-phenanthro[4,5-bcd]-
furan]-90-amine (7): mp 122-123 °C; 1H NMR (300 MHz,
CDCl3) δ 0.06-0.24 (m, 2H), 0.42-0.60 (m, 2H), 0.90-1.06
(m, 1H), 1.89 (dd, J = 6.0, 14.1 Hz, 1H), 1.96-2.10 (m, 1H),
2.18-2.34 (m, 1H), 2.47-2.70 (m, 3H), 2.79 (dd, J = 13.2, 14.7
Hz, 1H), 2.93 (dd, J = 6.9, 15.0 Hz, 1H), 3.61-3.73 (m, 1H),
3.86-4.12 (m, 3H), 3.87 (s, 3H), 4.28 (dt, J = 5.1, 6.3 Hz, 1H),
5.26 (q, J = 3.6 Hz, 1H), 6.58 (d, J = 8.1 Hz, 1H), 6.62 (d, J =
7.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 3.3, 3.4, 11.7, 26.0,
30.7, 33.1, 51.7, 56.8, 60.7, 65.3, 66.3, 85.6, 107.0, 113.6, 119.7,
123.7, 127.3, 129.1, 133.1, 143.0, 145.5; IR (KBr, cm-1) 3449,
2882, 1509, 1160, 1104, 951; HR-MS (DART) [M þ H]þ calcd
for C21H26NO4 356.1856, found 356.1865.
In conclusion, base treatment of oxazolidinone carboxylic
acid 6 led to the double decarboxylation reaction, affording
olefin 7. We examined the reaction mechanism and proposed
an E1cB-like mechanism via carbanion B but not via a
β-lactone intermediate. The double decarboxylation product
7 was converted into compound 17, which showed stronger
affinity for the μ receptor than morphine.
Acknowledgment. We acknowledge the financial support
from a Grant-in-Aid for Scientific Research (C) (19590105),
Shorai Foundation for Science, and the Uehara Memorial
Foundation. We also acknowledge the Institute of Instru-
mental Analysis of Kitasato University, School of Pharmacy
for its facilities.
Experimental Section
Double Decarboxylation Reaction of Compound 6. Under
argon, to a solution of compound 6 (4.3 g, 9.7 mmol) in DMF
(80 mL) was added potassium carbonate (2.9 g, 21.3 mmol) with
stirring at 60 °C for 15 h. The reaction mixture was poured into
distillated water and extracted with chloroform, and then dried
over anhydrous sodium sulfate. After removing the solvent under
reduced pressure, the residue was purified by crystallization from
Supporting Information Available: Experimental proce-
dures, characterization data for new compounds, discussion of
another possible mechanism, determination of the stereoche-
mistries of compounds 15 and 16, X-ray data for 7, and copies of
NMR spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
998 J. Org. Chem. Vol. 75, No. 3, 2010