Rapid access to morphinones: removal of 4,5-ether bridge with Pd-catalyzed triflate reduction

Article abstract of DOI:10.1016/j.tetlet.2010.02.146

A new synthetic method for the removal of the 4,5-bridged ether moiety of several opioids has been developed. This process offers a faster, simpler synthetic route to obtain the morphinone scaffold in high yields without the need for protection of the ketone moiety.

Full text of DOI:10.1016/j.tetlet.2010.02.146

Tetrahedron Letters 51 (2010) 2359–2361
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Rapid access to morphinones: removal of 4,5-ether bridge with Pd-catalyzed
triflate reduction
*
Christopher D. Hupp, John L. Neumeyer
Medicinal Chemistry Program, Alcohol and Drug Abuse Research Center, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, MA 02478, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A new synthetic method for the removal of the 4,5-bridged ether moiety of several opioids has been
developed. This process offers a faster, simpler synthetic route to obtain the morphinone scaffold in high
yields without the need for protection of the ketone moiety.
Received 26 January 2010
Revised 22 February 2010
Accepted 23 February 2010
Available online 1 March 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Opioids such as morphine (1) and codeine (2) (Fig. 1) and ana-
logs offer a wealth of therapeutic benefit as analgesics and as
building blocks for valuable therapeutics.1–3 Opioid analgesics such
as hydrocodone (3) and oxycodone (4) (Fig. 1) are used to treat in-
tense pain1 while the opioid, naltrexone (5, Fig. 1), is used to aid in
reducing opioid dependence.4–6 More facile synthetic methods to
gain access to new opioid analogs can offer the opportunity to dis-
cover potentially useful opioid therapeutics.
using iodomethane and potassium carbonate to yield derivatives
729 and 8, respectively. Hydrocodone (3), oxycodone (4), 7, and 8
were then reduced to their phenol derivatives (9–12) using zinc
under acidic conditions.7,11,30 Finally, the triflates (13–16) were
obtained after treating phenols (9–12) with N-phenylbis(trifluoro-
methanesulfonate)amide and cesium carbonate or sodium hydride
(see Supplementary data for details).
The reduction of the opioid-4-triflates (13–16) was initially at-
tempted using 10% Pd/C, Mg, and NH4OAc.28 However, in our
hands, this reduction protocol failed to afford any product. Success
was achieved when 10% palladium acetate, 10% diphenylphosphi-
nopropane (dppp), and 2.5 equiv of triethylsilane25 at 60 °C for
4 h was used to produce the desired morphinones (17–19, Table 1).
As shown in Table 1, the reduction worked very well for opioid-
4-triflates (13, 15 and 16) affording yields of 90–95% of morphi-
none products (17–19, respectively). The naloxone triflate (14),
which contained an N-allyl moiety, produced multiple byproducts
under these reaction conditions and no product was isolated.
Opioids without the 4,5-ether bridge (referred to as morphinon-
es, Fig. 1) are of particular interest due to their novel biological and
pharmacological properties.7–11 The only reported method used to-
day to remove the 4,5-ether bridge7–13 was originally described by
Sawa and co-workers in the 1960s and uses ammonia gas and solid
sodium metal.14,15 This synthetic route involves multiple steps,
including protection and deprotection of the ketone moiety, result-
ing in a low overall yield of the final morphinone product.7–15
A
shorter, higher yielding alternative route to these intriguing com-
pounds would be quite valuable and necessary to access the mor-
phinone scaffold efficiently making them readily available for
pharmacological and biological evaluations.
In a continuing effort in our laboratory to synthesize novel kappa
opioid agonists and mixed kappa/mu agonists for the treatment of
drug abuse,11,16–22 we have developed an efficient synthetic route
that allows easier access to this pharmacologically important class
of compounds. Our method for the synthesis of the morphinone
scaffold includes a palladium-catalyzed aryl triflate reduction. In
general, aryl triflate reductions are highly precendented23–28 and
were believed to be applicable to our substrates. Furthermore, this
transformation could circumvent the ketone protection/deprotec-
tion sequence needed in Sawa’s synthesis.14,15
N
R1
N
R2
4
5
O
RO
OH
1:
2:
R = H; morphine
R = Me; codeine
O
RO
O
3: R = Me, R1 = Me, R2 = H; hydrocodone
4: R = Me, R1 = Me, R2 = OH; oxycodone
R1
N
R = H, R1 = CPM, R2 = OH; naltrexone
5:
R2
The opioid-4-triflates used in the palladium-catalyzed reduc-
tion were synthesized according to Scheme 1, shown below. The
phenol moiety of naltrexone (5) and naloxone (6) was methylated
RO
O
Morphinone
* Corresponding author. Tel.: +1 617 855 3388; fax: +1 617 855 3585.
E-mail address: jneumeyer@mclean.harvard.edu (J.L. Neumeyer).
Figure 1. Structures of opioids (CPM = cyclopropylmethyl).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.146

2360
C. D. Hupp, J. L. Neumeyer / Tetrahedron Letters 51 (2010) 2359–2361
Table 1
R
R
N
N
Reduction of opioid-4-triflates to morphinone products
OH
R1
R
N
R1
R
MeI, K2CO3
DMF, rt, 17 h
N
R1
Pd(OAc)2 (10 mol%),
O
dppp (10 mol%)
O
HO
5:
O
MeO
7: R = CPM, R1 = OH; 95%
8:
O
Et3SiH (2.5 eq.), DMF,
60°C, 4 h
R = CPM; naltrexone
6: R = Allyl; naloxone
R = Allyl, R1 = OH; 80%
3: R = Me, R1 = H; hydrocodone
R = Me, R1 = OH; oxycodone
MeO
OTf
O
MeO
O
13-16
17-19
4:
Triflate
R
R1
Yield (%)
Morphinone
Zn, HCl, AcOH
or Zn, NH4Cl/ROH,
reflux, 3-4 h
13
14
15
16
CPM
Allyl
Me
OH
OH
H
94
0
95
90
17
NA
18
19
R
N
Me
OH
R
N
R1
R1
PhN(Tf)2,
Cs2CO3 or NaH
THF, rt, 15 h
In conclusion, we have developed a new alternate synthetic
route to remove the 4,5-ether bridge of opioids (3–5). Through
the utilization of an opioid-4-triflate intermediate and subsequent
palladium-catalyzed reduction, we were able to present a viable
pathway to a class of pharmacologically important molecules. Fur-
ther studies on this intriguing class of compounds are currently
underway.
MeO
OH
O
MeO
OTf
O
9: R = CPM, R1 = OH; 36%
13:
R = CPM, R1 = OH; 70%
10:
R = Allyl, R1 = OH; 67%
11: R = Me, R1 = H; 69%
12:
14: R = Allyl, R1 = OH; 71%
15: R = Me, R1 = H; 73%
R = Me, R1 = OH; 53%
16:
R = Me, R1 = OH; 70%
Scheme 1. Synthesis of opioid-4-triflates.
Acknowledgments
R
R
AR
This work was supported in part by NIH grants T32-DA007252
(C.D.A.) and R01-DA14251 (J.L.N.).
N
N
R1
R1
PhN(Tf)2,
Cs2CO3 or NaH
Supplementary data
THF, rt, 15 h
70-73%
MeO
OH
9, 11, 12
O
MeO
OTf
O
Supplementary data (experimental details and characterization
for compounds 7–19) associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.02.146.
Pd(OAc)2, dppp
Et3SiH, DMF, 60°C,
4 h, 90-95%
PhBr, Cu,
Cs2CO3, Pyr.
6-15 h, 40-84%
ref s. 8,11,
12,15
R
N
R1
References and notes
R
N
R1
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