Selective protection and functionalization of morphine: Synthesis and opioid receptor binding properties of 3-amino-3-desoxymorphine derivatives

Article abstract of DOI:10.1021/jm000119i

As part of an effort to identify novel opioid receptor interactive agents, we recently prepared a series of 8-(substituted)amino analogues of cyclazocine. We found the chiral 8-phenylamino (NHC₆H₅) cyclazocine derivative to have subn

Full text of DOI:10.1021/jm000119i

3558
J . Med. Chem. 2000, 43, 3558-3565
Selective P r otection a n d F u n ction a liza tion of Mor p h in e: Syn th esis a n d Op ioid
Recep tor Bin d in g P r op er ties of 3-Am in o-3-d esoxym or p h in e Der iva tives†,1
Mark P. Wentland,*,‡ Wenhu Duan,‡ Dana J . Cohen,§ and J ean M. Bidlack§
Department of Chemistry, Rensselaer Polytechnic Institute, Troy, New York 12180, and Department of Pharmacology and
Physiology, School of Medicine and Dentistry, University of Rochester, Rochester, New York 14642
Received March 10, 2000
As part of an effort to identify novel opioid receptor interactive agents, we recently prepared
a series of 8-(substituted)amino analogues of cyclazocine. We found the chiral 8-phenylamino
(NHC6H5) cyclazocine derivative to have subnanomolar affinity for κ opioid receptors and a
2-fold lower affinity for µ opioid receptors. To determine if the benefits of (substituted)amino
groups could be extended to the morphine core structure, we have made five novel 3-amino-
3-desoxymorphine derivatives of general structure 5 where RR′N ) H2N, CH3NH, (CH3)2N,
C6H5NH, and C6H5CH2NH. Relative to morphine, these derivatives had 38-273-fold, 11-41-
fold, and 10-141-fold lower affinity for µ, δ, and κ opioid receptors, respectively. Target
compounds were made via Pd-catalyzed amination of a morphine 3-trifluoromethylsulfonate
substrate where the 6-OH group was protected with a tert-butyldiphenylsilyl group. To make
6-tert-butyldiphenylsilyloxymorphine selectively, a new high-yield method was developed
whereby morphine was bis-silylated using normal conditions followed by selective removal of
the 3-tert-butyldiphenylsilyl group with catalytic tetrabutylammonium fluoride.
In tr od u ction
We recently reported the opioid receptor binding
properties of a series of cyclazocine analogues (1) where
the 8-OH group of cyclazocine (2) was replaced with
amino groups.2 Several members of this new series had
surprisingly high affinity for µ and κ receptors based
on existing SAR knowledge and doctrine.3,4 For mor-
phine (3) and the numerous compounds derived from
its structure (e.g., cyclazocine and other benzomor-
phans), the phenolic OH group was historically thought
to be a stringent requirement for binding to opioid
receptors serving as a putative H-bond donor to a
complementary site on the protein.3-8 For example, in
two recent studies, the 3-OH group of morphine7 and
natrindole8 was replaced by H, alkyl, acetyl, aryl, and/
or heteroaryl groups; all targets had substantially
port this speculation, and additional SAR and compu-
tational data are being collected to confirm our belief.
diminished affinity for opioid receptor relative to their
3-OH counterparts. In a recent report, the 3-OH of
naltrexone and oxymorphone was replaced by methane-
sulfonamido, a standard phenolic bioisostere.9 These
replacements abolished opiate activity.
Data from our study corroborate the need for H-bond
donation by the 8-substituent, but due to the expanded
valence of N (versus O), we found that certain mono-
N-substituents (e.g., (-)-(2R,6R,11R)-4) enhance bind-
ing affinity relative to the 8-NH2 analogue.2 We specu-
late that the N-substituent occupies an accessory binding
site on the receptor protein and that affinity is enhanced
via specific molecular contacts. Preliminary data sup-
Prior to publication of our recent paper,2 opioid
receptor binding data for 8-aminobenzomorphans (1)
have never been reported to our knowledge. Several
members of the series, however, date back to the 1970s
where we had used this 8-OH f NH2 conversion to
improve the pharmacodynamic properties of cyclazocine
(2).10 Cyclazocine was evaluated in humans in the 1960s
† This manuscript is dedicated to the memories of Professors
Sydney Archer and Arthur G. Schultz.
* To whom correspondence should be addressed. Phone: (518) 276-
2234. Fax: (518) 276-4887. E-mail: wentmp@rpi.edu.
‡ Rensselaer Polytechnic Institute.
§ University of Rochester.
10.1021/jm000119i CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/01/2000

Selective Protection/ Functionalization of Morphine
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 19 3559
and early 1970s as an analgesic and as a possible
treatment for preventing relapse in post-addicts of
heroin.11,12 In humans dosed with the drug, potent
analgesia was observed, and following abrupt cyclazo-
cine withdrawal, patients did not display drug-seeking
behavior. Further clinical development of cyclazocine
was ceased due, in part, to a short duration of analgesic
action.11,12 Cyclazocine is O-glucuronidated in humans
which may account for its short duration of action.10 In
an attempt to retard this metabolic inactivation and
increase its duration of action, we discovered some years
ago that replacement of the 8-OH group of 2 with NH2
provided the novel racemic compound 1 (R ) R′ ) H)
which had somewhat diminished antinociception po-
tency in mice when delivered by the subcutaneous route
but comparable (to 2) efficacy when delivered orally.10
For example, in the mouse acetylcholine writhing test,
the po/sc ratio of ED50 values for cyclazocine was 35,
and for 1 (R ) R′ ) H) this ratio was 4 indicating the
8-OH f NH2 change accounted for higher oral efficacy.
Whether high oral bioavailability due to lower first-pass
metabolism, higher gut wall permeability, reduced
clearance, or some other factor accounts for the higher
(than would be predicted by sc data) oral efficacy of 1
(R ) R′ ) H) is not known.
co-workers17 gave us rapid entry into our initial set of
diverse target compounds. For the present study, the
requisite morphine 3-triflate (6, R1 ) H, R3 ) OSO2-
CF3, R6 ) OH) is a known compound prepared in high
yield by treating morphine with triethylamine and
N-phenyltrifluoromethanesulfonimide.7,18,19 This com-
pound was subsequently used as substrate for Pd-
catalyzed alkyl and (hetero)aryl coupling reactions and
as an intermediate to apomorphine derivatives. The
naltrexone 3-triflate was also made; it was converted
to 3-cyano-3-deoxynaltrexone via a Pd-catalyzed cya-
nation reaction20 and to 3-alkyl and (hetero)aryl ana-
logues of naltrindole.8
The Pd-catalyzed couplings reported for morphine
3-triflate and naltrexone 3-triflate did not involve
strongly basic conditions. Since the use of strong base
(NaOt-Bu) gave superior results in our Pd-catalyzed
aminations of cyclazocine triflate, we felt our needs for
the present study would be better served if the morphine
3-triflate substrate had the potentially troublesome
6-OH protected with a group stable to our reaction
conditions. Thus, having a triflate substrate amenable
to a variety of amine co-reactants and Pd-catalyzed
amination conditions would allow us to broaden the
scope of our study as guided by a developing SAR.
Our primary goal for this study was to determine if,
as we found in our benzomorphan study, NH2 is a
bioisosteric replacement for the 3-OH of morphine at
opioid receptors. In addition, we also wanted to deter-
mine if opioid binding was sensitive to the substitution
pattern on the 3-amino group. To accomplish this goal
we set out to synthesize and evaluate, in opioid binding
assays, a small series of morphine analogues of general
structure 5 where the 3-OH group of the alkaloid is
replaced by amino and (substituted)amino groups.
Besides the 3-methanesulfonamido analogues of
naltrexone and oxymorphone,9 the only other 3-amino-
3-desoxymorphine derivatives in the literature to our
knowledge are several 3-aminodextromorphan ana-
logues.13 These compounds, however, have the opposite
stereochemistry to natural opiates and were studied for
other (than opioid receptor binding) pharmacological
properties.13,14 We now report the synthetic methods,
µ, δ and κ opioid binding data, and inhibition of adenylyl
cyclase activity for these new morphine analogues. We
also report comparative opioid receptor binding data for
morphine, the (-)-form of cyclazocine, and two optically
active 8-aminocyclazocine derivatives.
The 3-triflate (6, R1 ) H, R3 ) OSO2CF3, R6 ) OAc)
of known morphine 6-acetate21-23 would not be useful
due to the likelihood of 6-acetate cleavage by NaOt-Bu
and/or involvement of the allylic acetate in Pd-mediated
π-allyl complex formation. The logical alternative was
a 6-silyloxy protecting group. Silylation of morphine
with trimethylsilyl chloride or tert-butyldimethylsilyl
chloride is well-known to give 3,6-disubstituted prod-
ucts.24,25 Seltzman and co-workers similarly converted
1-iodomorphine (6, R1 ) I, R3 ) R6 ) OH) to the corre-
sponding 3,6-bis-tert-butyldimethylsilyl ether in 92%
yield.26 They were also able to make each mono-tert-
butyldimethylsilyl ether; however, they were not formed
selectively. For example, when 1-iodomorphine was
treated with N-(tert-butyldimethylsilyl)-N-methyltrif-
luoroacetamide, the 6-monosilyl ether 6 (R1 ) I, R3 )
OH, R6 ) OSi(CH3)2t-Bu) was isolated in 8.7% from a
mixture of starting material and both mono- and bis-
silyl ether derivatives.
We chose an alternate approach to prepare the
morphine 6-silyl ether intermediate we needed for
subsequent 3-OH triflate formation, namely to make the
3,6-bis-silyl ether followed by selective deprotection of
the phenolic (i.e., better leaving group) 3-OH moiety.
This standard synthetic tack has been used, for ex-
ample, in making morphine 6-acetate selectively21 and
to differentiate between the aromatic and aliphatic
amines in our early 8-aminobenzomorphan studies.10
The 6-monoglucuronide of morphine has also been made
selectively,27,28 and in one instance, a selective removal
of the 3-glucuronide group from morphine 3,6-diglucu-
ronide was accomplished using an enzyme.29 We have
reduced this stepwise selective protection approach to
practice by making the novel morphine 6-tert-butyl-
diphenylsilyl ether 8 in 84% yield from morphine. These
results as well as the conversion of 8 to our desired
3-amino-3-desoxymorphine targets 16-20 are sum-
marized in Scheme 1.
Ch em istr y
Our approach to make the desired 3-amino-3-desoxy-
morphine targets 5 centered around our methodology
to make the 8-aminocyclazocine analogues, namely the
Pd-catalyzed amination of the appropriate aryl tri-
flate.2,15 This powerful amination procedure pioneered
by Buchwald and co-workers16 and Hartwig and

3560 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 19
Wentland et al.
Sch em e 1. Syntheses of 3-Amino-3-desoxymorphine Derivatives
Morphine (3) was treated with excess tert-butyldiphe-
nylsilyl chloride (TBDPSCl) and imidazole to give
morphine 3,6-bis-tert-butyldiphenylsilyl ether (7) in
nearly quantitative yield. Exposure of 7 to 0.25 equiv
of tetrabutylammonium fluoride (TBAF, 1 M in THF
containing 5% H2O) for 1 h at 25 °C gave, after purifi-
cation by flash chromatography, a 84.1% yield of mor-
phine 6-tert-butyldiphenylsilyl ether (8). This chroma-
tography was done to provide material for character-
ization purposes; otherwise the crude product of this
reaction, obtained in 97% yield, could be used in the next
step without any compromise in yield. While all spectral
and combustion data were consistent with the structural
assignment of 8 as the mono-6-tert-butyldiphenylsilyl
ether, we could not prove that the TBDPS group was
at the 6-position versus the 3-position. We therefore
prepared 8 by an independent route to confirm struc-
ture. Morphine 3-acetate30 was converted to 6 (R1 ) H,
R3 ) OAc, R6 ) OSiPh2t-Bu) using TBDPSCl/imidazole.
Subsequent base-induced hydrolysis of this ester pro-
vided 8 identical in all respects with 8 made via the
selective protection approach shown in Scheme 1.
The role of TBAF in this selective deprotection is an
interesting one in that much less than 1 equiv of TBAF
gave the best results. When 1 full equiv of TBAF (1 M
in THF containing 5% H2O, 15 min, 25 °C) was used,
both 3- and 6-TBDPS groups were cleaved. When 0.1
equiv TBAF was used under the same conditions, only
the more reactive 3-TBDPS group was cleaved due to
the better leaving group properties of the phenolic OH.
We found the best yields were obtained when 0.25 equiv
of TBAF was used at 25 °C for 15-60 min. The water
present in the mixture may play an important role in
the catalytic nature of the reaction conditions by, for
example, hydrolyzing TBDPSF (from fluoride induced
cleavage of 3-TPDPS group from 7) to TBDPSOH and
HF. The HF can then be converted to TBAF (along with
the neutral phenol) which can then promote another
desilylation of 7 completing one catalytic cycle. Since
the nearly quantitative transformation of 7 to 8 filled
our needs very well, we did not investigate other
methods (e.g., anhydrous TBAF, other silyl groups) of
selective deprotection.
Compound 8 was converted to the corresponding
3-triflate derivative 9 in quantitative yield using stan-
dard conditions. Triflate 9 was aminated using two
known Pd-catalyzed amination methods.16,17 In one, Pd-
(OAc)2 and BINAP were used as catalyst source and Pd
ligand, respectively,16 while the other procedure17 used
Pd2(dba)3 and DPPF.31 Both were performed in toluene
at 80 °C and 1 equiv of NaOt-Bu was required for
satisfactory yields. The use of Cs2CO3 as base was also
reported to give satisfactory results;32 however, we
found like others15 that NaOt-Bu gave much higher
yields. As noted by Buchwald,16 we also observed that
NaOt-Bu-induced cleavage of the triflate to the corre-
sponding phenol competed with amination. This re-
sulted in somewhat lower yields in those aminations
that were relatively slow. Thus, exposure of 9 to
methylamine, dimethylamine, aniline, or benzylamine
using one of the amination methods described above and
in the Experimental Section gave aminated products
12-15, respectively, in yields ranging from 26% to 84%.
Treatment of 12-15 with 1.5 equiv of TBAF in THF at
25 °C for a much longer period (6-12 h) than used to
cleave the 3-TBDPS ether gave the corresponding
targets 17-20 in 79-96% yields. The primary amino
analogue 16 was made by first coupling 9 with Ph2Cd
NH following a modification of a known procedure32 to
provide 10 (Scheme 1). Compound 10 was subjected to
imine-exchange conditions (hydroxylamine) to provide
11, and subsequent deprotection gave target 16. The
overall yield for the three steps in converting 9 to 11
was 42%.

Selective Protection/ Functionalization of Morphine
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 19 3561
Ta ble 1. Opioid Receptor Binding Data for 3-Amino-3-desoxymorphine Derivatives
Ki (nM ( SE)a versus
receptor selectivityb
compd
R
R′
[3H]DAMGO (µ)
[3H]naltrindole (δ)
[3H]U69,593 (κ)
µ:δ
µ:κ
κ:δ
3 (morphine)
0.88 ( 0.14
53 ( 3.0
140 ( 18
2400 ( 190
5700 ( 1100
1600 ( 110
1500 ( 100
5500 ( 190
0.58 ( 0.06
12 ( 2.3
24 ( 2.3
740 ( 75
156
45
90
7
25
167
6
27
14
44
1
4
103
0.5
0.7
0.5
6
3
2
6
6
16
17
18
19
20
21c
22c
4c
H
H
CH3
H
H
H
CH3
CH3
C6H5
63 ( 15
2800 ( 420
290 ( 8.1
240 ( 16
59 ( 3.7
33 ( 5.1
0.10 ( 0.03
1.8 ( 0.12
1.1 ( 0.08
240 ( 23
CH2C6H5
3400 ( 540
0.052 ( 0.009
1.2 ( 0.13
0.54 ( 0.01
2
RR′N ) OH
11
10
10
H
H
H
C6H5
7
5
5.2 ( 0.08
a
b
See Experimental Section. Receptor selectivity is expressed as the ratio of the corresponding Ki values. c See ref 2.
Resu lts
Opioid receptor binding data for 8-amino-3-desoxy-
compound was slightly improved (3-fold) relative to 16
and significantly improved (10-fold) relative to 17. For
compound 18, the µ:κ selectivity ratio is 1 suggesting
that a dimethylamino group imparts greater κ affinity
than for primary amino (µ:κ ) 14) or methylamino (µ:κ
) 44) analogues. The µ:κ selectivity ratio of 1 for
compound 18 is more in line with our benzomorphan
studies where we found that the 8-amino and most
(monosubstituted)amino or (disubstituted)amino ana-
logues displayed µ:κ selectivity ratios of 0.5-2.
In the benzomorphan study, the 8-PhNH (e.g., 4 in
Table 1; Ki ) 0.54 nM versus κ) and 8-PhCH2NH ana-
logues had generally higher affinity for µ, δ, and κ
receptors relative to other 8-(monosubstituted)amino
derivatives. When these same appendages were intro-
duced into the 3-position of morphine to give 19 and 20,
respectively, affinity for µ and δ was not significantly
different from 3-NH2 or 3-CH3NH derivatives, 16 and
17, respectively; for the κ receptor, the affinity of 19 was
somewhat greater, while for 20, affinity was lower. The
µ:δ and µ:κ selectivity ratios for the 3-PhNH derivative
19 were close to those of the 3-(CH3)2N derivative 18
which were the lowest (i.e., poor selectivity) within the
morphine series. This observation contrasts the data for
the 8-PhCH2NH analogue 20 which had the highest µ:δ
and µ:κ selectivity ratios (i.e., highest µ selectivity) in
the series.
morphine targets 16-20 compared to morphine (3)
are found in Table 1. For further comparison pur-
poses, opioid binding affinities for the active enanti-
omers of three benzomorphans from our previous study,
(-)-cyclazocine (21) and the corresponding 8-amino (22)
and 8-phenylamino (4) analogues, are also included.
Standard radioligand displacement assays were used
to assess the affinity and selectivity of test com-
pounds for µ ([3H]DAMGO), δ ([3H]naltrindole), and κ
([3H]U69,593) opioid receptors in guinea pig membranes
(see Experimental Section). For analysis of the binding
data, affinity differences of higher than 2-fold are
considered significantly different.
The primary amino analogue 16 has good affinity for
the µ receptor (Ki ) 53 nM), however, affinity was 60-
fold lower than that observed with morphine. In the
benzomorphan series, the 8-NH2 analogue 22 also
displayed high affinity for µ and was 18-fold less potent
than the (-)-cyclazocine (21). Morphine is well-known
to have much higher affinity for µ than for δ or κ as
evidenced by the selectivity data shown in Table 1
where morphine has a µ:δ and µ:κ selectivity ratio of
156 and 27, respectively. Between δ and κ, morphine
has higher affinity for κ (κ:δ ) 6). Compound 16, the
primary amino derivative, also has substantially less
affinity for δ and κ, but the µ:δ, µ:κ, and κ:δ ratios are
somewhat lower (2-3-fold) than for morphine suggest-
ing that the NH2 group accounts for slightly greater
relative binding to δ and κ than the prototypic 3-OH.
This trend was not evident within the benzomorphan
series where the 8-OH and NH2 derivatives had nearly
identical µ:δ, µ:κ, and κ:δ ratios.
To determine whether these aminomorphine ana-
logues were agonists or antagonists, the compounds
were tested to determine if they would inhibit adenylyl
cyclase activity in membranes from the human
SH-SY5Y neuroblastoma cell line. The compounds were
tested at a final concentration of 10 µM and were
compared to the µ-selective ligand DAMGO. As shown
in Table 2, all of the compounds inhibited cyclic AMP
levels, indicating that all the morphine derivatives
were agonists. The inhibition by these compounds was
lower than was observed with DAMGO. The fact that
the compounds have significantly lower affinity than
DAMGO, which has affinity in the nanomolar range,
would account for the reduced inhibition of cyclic AMP
production.
When the primary amine of 16 was substituted with
one methyl group to give 17, binding affinity for µ and
δ did not change significantly; however, 17 had 4-fold
lower affinity for the κ receptor than 16. When compar-
ing the dimethylamino analogue 18 to either 16 or 17,
affinity for µ decreased 4-fold; for δ receptors, affinity
was similar; and for κ, affinity of the dimethylamino

3562 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 19
Wentland et al.
Ta ble 2. Inhibition of Adenylyl Cyclase Activity by
3-Amino-3-desoxymorphine Derivatives
able to the phenolic OH-containing ligands due to the
lower valence of oxygen compared to nitrogen.
% inhib of cyclic AMP
compd
16
17
18
19
20
DAMGO
accumulation ( SEa
Exp er im en ta l Section
Proton NMR and in certain cases 13C NMR [Varian Unity-
500 (500 MHz) NMR] data, direct insertion probe (DIP)
chemical ionization mass spectra (Shimadzu GC-17A GC-MS
mass spectrometer), and infrared spectra (Perkin-Elmer Para-
gon 1000 FT-IR spectrophotometer) were consistent with the
26 ( 5.8
29 ( 11
13 ( 3.8
44 ( 3.2
17 ( 9
58 ( 4.2
1
assigned structures. Complete H NMR data are reported for
all new compounds. 1H NMR multiplicity data are denoted by
s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet),
and br (broad). Coupling constants are in hertz (Hz). Carbon,
hydrogen, and nitrogen elemental analyses were performed
by Quantitative Technologies Inc., Whitehouse, NJ , and were
within (0.4% of theoretical values. Melting points were
determined on a Meltemp capillary melting point apparatus
and are uncorrected. Optical rotation data were obtained from
a Perkin-Elmer 241 polarimeter. Reactions were generally
performed under a N2 atmosphere. For Pd-catalyzed amination
reactions, an oven-dried flask equipped with reflux condenser
was placed into an N2 filled glovebox or bag where it was
charged with NaOt-Bu and either Pd2(dba)3 and DPPF or Pd-
(OAc)2 and BINAP. The system was capped with rubber septa
and removed from the glovebox/bag where dry toluene
(distilled from Na, benzophenone ketyl) was added via syringe.
BINAP [2,2′-bis(diphenylphosphino)-1,1′-binaphthyl] and NaOt-
Bu were purchased from Sigma-Aldrich, and Pd2(dba)3 [tris-
(dibenzylideneacetone)dipalladium(0)], DPPF [1,1′-bis(diphe-
nylphosphino)ferrocene] and Pd(OAc)2 were purchased from
Strem Chemicals, Inc.
7,8-Did eh yd r o-3,6-bis[[(1,1-d im eth yleth yl)d ip h en ylsi-
lyl]oxy]-4,5-ep oxy-17-m eth yl-(5r,6r)-m or p h in a n (7). To a
mixture of morphine hydrate (1.0 g, 3.3 mmol), imidazole
(1.032 g, 15.2 mmol), and CH2Cl2 (20 mL) was added TBDPSCl
(2.0 mL, 7.6 mmol) at 25 °C. The mixture was stirred at 25 °C
for 1 h and diluted with CH2Cl2 (50 mL). The resulting mixture
was washed with brine (30 mL), dried (Na2SO4) and concen-
trated on a rotary evaporator. The residue was purified by
flash column (silica gel; CH2Cl2:MeOH ) 20:1) to give 2.5 g
(99.5%) of 7 as a oil: 1H NMR (CDCl3) δ 7.95-7.73 (m, 8H),
7.52-7.32 (m, 12H), 6.35 (d, 1H, J ) 8.1 Hz), 6.19 (d, 1H, J )
8.1 Hz), 5.87 (d, 1H, J ) 9.8 Hz), 5.20 (dt, 1H, J ) 2.7, 9.8
Hz), 4.61 (d, 1H, J ) 7.4 Hz), 4.24-4.23 (m, 1H), 3.27 (dd, 1H,
J ) 2.9, 6.1 Hz), 2.94 (d, 1H, J ) 18.8 Hz), 2.52 (dd, 1H, J )
4.2, 11.8 Hz), 2.45-2.44 (m, 1H), 2.41-2.36 (m, 1H), 2.39 (s,
3H), 2.22 (dd, 1H, J ) 6.6, 8.8 Hz), 1.82-1.75 (m, 2H), 1.21 (s,
9H), 1.20 (s, 9H). Anal. (C49H55NO3Si2) C, H, N.
7,8-Dideh ydr o-6-[[(1,1-dim eth yleth yl)diph en ylsilyl]oxy]-
4,5-ep oxy-17-m eth yl-(5r,6r)-m or p h in a n -3-ol (8). To a mix-
ture of 7 (2.0 g, 2.62 mmol) and THF (20 mL) was added TBAF
(0.656 mL of 1 M in THF containing 5% H2O, 0.656 mmol) at
25 °C. After stirring at 25 °C for 1 h, water (100 mL) was added
and the mixture was extracted with CH2Cl2 (50 mL × 3). The
organic layer was washed with brine (50 mL), dried (Na2SO4)
and concentrated on a rotary evaporator. The residue was
purified by flash column (silica gel; CH2Cl2:MeOH ) 20:1) to
give 1.15 g (84.1%) of 8 as a foam: 1H NMR (CDCl3) δ 7.76-
7.66 (m, 4H), 7.43-7.33 (m, 6H), 6.61 (d, 1H, J ) 8.1 Hz),
5.68-5.66 (m, 1H), 5.15-5.13 (m, 1H), 4.41 (d, 1H, J ) 5.8),
4.24-4.22 (m, 1H), 3.35 (dd, 1H, J ) 3.1, 6.1 Hz), 2.92 (d, 1H,
J ) 18.8 Hz), 2.54 (dd, 1H, J ) 4.4, 12.0 Hz), 2.49 (s, 1H),
2.38 (s, 3H), 2.33 (dt, 1H, J ) 3.4, 12.4 Hz), 2.23 (dd, 1H, J )
6.3, 18.8 Hz), 1.78 (dt, 1H, J ) 5.1, 12.7 Hz), 1.61 (d, 1H, J )
11.2 Hz); MS m/z 524 (MH+). Anal. (C33H37NO3Si) C, H, N.
7,8-Dideh ydr o-6-[[(1,1-dim eth yleth yl)diph en ylsilyl]oxy]-
4,5-ep oxy-17-m eth yl-(5r,6r)-m or p h in a n -3-ol, 3-(Tr iflu o-
r om eth a n esu lfon a te) (9). To a mixture of 8 (3.95 g, 7.5
mmol), pyridine (2.5 mL, 30 mmol) and CH2Cl2 (50 mL) was
added triflic anhydride (2.54 mL, 15 mmol) at 0 °C. The
mixture was stirred at 0 °C for 2 h, diluted with CH2Cl2 (50
mL), washed with brine (60 mL) and dried (Na2SO4). After
removal of the solvent on a rotary evaporator and drying in
vacuo, compound 9 (foam, 4.75 g, 100%) was characterized by
a
See Experimental Section.
Con clu sion s
One of the most important questions we wanted
answered in this study was if the 3-NH2 group was an
effective bioisosteric replacement for the prototypic
3-OH group of morphine. The answer, in a broad sense,
appears to be yes. While it can be argued that the 3-NH2
analogue 16 has 60-fold lower affinity for µ than
morphine, in an absolute sense 16 has significant
affinity (Ki ) 53 nM) for the receptor. After comparing
this result with the corresponding data from our ben-
zomorphan study, the OH f NH2 replacement is ap-
parently more effective for µ affinity in the cyclazocine
core structure than in morphine. There appears to be
another difference between the SARs noted in the
benzomorphan and morphine series. The difference is
in the role of phenyl-containing amino appendages. For
benzomorphans, these substitutions are beneficial (com-
pared to 8-NH2) for µ and κ binding, while in the
morphine series, little advantage is seen. Similar to
what was observed in the benzomorphan series, di-
methylamino substitution (i.e., 18) results in substan-
tially reduced binding affinity to the µ receptor. All of
the aminomorphine analogues were agonists, like mor-
phine. Therefore, the substitution of 3-amino groups for
the 3-OH group in morphine did not change the ago-
nistic properties associated with morphinans
From these data, it seems reasonable to conclude that
the 3-amino- and 3-(monosubstituted)amino-3-desoxy-
morphine derivatives interact with the µ opioid receptor
in a manner similar to morphine, especially with respect
to the putative H-bond donor ability the 3-substituent.
Further support for this conclusion stems from the 4-fold
lower affinity observed for the 3-dimethylamino ana-
logue 18 for µ. This compound can be an H-bond donor
when protonated; however, the low pKa (<5) for such
aromatic amines decreases their likelihood of any
significant protonation at the pH (7.5) of the assay.
Within this series, the 3-dimethylamino analogue 18
has very close to the highest affinity for κ receptors. This
result represents a divergence in κ binding SAR from
our benzomorphan study where it was found that the
amino, methylamino, phenylamino, and benzylamino
analgoues all had higher (up to 60-fold) affinity than
the dimethylamino analogue. We have no explanation
to account for this divergent SAR.
We will continue to explore this new opportunity in
understanding opioid SAR by replacing the phenolic OH
groups of other benzomorphan and morphinan deriva-
tives with amino and (substituted)amino groups. Be-
sides their ability to donate the putatively required
H-bond, these appendages also hold the prospect of
accessory binding of the N-substituent to a complimen-
tary site on the protein. This site is obviously unavail-

Selective Protection/ Functionalization of Morphine
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 19 3563
1H NMR and used without additional purification: 1H NMR
(CDCl3) δ 7.82-7.80 (m, 1H), 7.68-7.66 (m, 2H), 7.47-7.34
(m, 6H), 6.92 (d, 1H, J ) 8.6 Hz), 6.56 (d, 1H, J ) 8.3 Hz),
5.74-5.72 (m, 1H), 5.17 (dt, 1H, J ) 2.7, 9.8 Hz), 4.51 (d, 1H,
J ) 5.9 Hz), 4.18-4.16 (m, 1H), 3.27 (dd, 1H, J ) 3.1, 5.8 Hz),
3.02 (d, 1H, J ) 19.0 Hz), 2.49 (dd, 1H, J ) 3.1, 12.2 Hz), 2.43-
2.41 (m, 1H), 2.36 (s, 3H), 2.31-2.24 (m, 2H), 1.74 (dt, 1H, J
) 5.1, 12.2 Hz), 1.71-1.70 (m, 1H), 1.11 (s, 9H).
(d, 2H, J ) 6.8 Hz), 7.69 (d, 2H, J ) 6.8 Hz), 7.33-7.45 (m,
6H), 6.49 (d, 1H, J ) 8.0 Hz), 6.43 (d, 1H, J ) 8.0 Hz),5.74-
5.72 (m, 1H), 5.19-5.17 (m, 1H), 4.36 (d, 1H, J ) 5.9 Hz),
4.23-4.21 (m, 1H), 3.30 (dd, 1H, J ) 3.2, 6.1 Hz), 2.93 (d, 1H,
J ) 23.7 Hz), 2.86 (s, 3H), 2.54-2.51 (m, 1H), 2.47-2.45 (m,
1H), 2.45-2.41 (m, 1H), 2.40 (s,3H), 2.28 (dd, 1H, J ) 6.1, 23.7
Hz), 1.76 (dt, 1H, J ) 4.8, 12.2 Hz), 1.70-1.68 (m, 1H); MS
m/z 537 (MH+).
N-(Dip h en ylm eth ylen e)-7,8-d id eh yd r o-6-[[(1,1-d im eth -
ylet h yl)d ip h en ylsilyl]oxy]-4,5-ep oxy-17-m et h yl-(5r,6r)-
m or p h in a n -3-a m in e (10). A mixture of 9 (300 mg, 0.48
mmol), DPPF (40 mg, 0.07 mmol), Pd2(dba)3 (22 mg, 0.024
mmol), NaOt-Bu (55 mg, 0.57 mmol), Ph2CdNH (96 µL, 0.57
mmol) and toluene (19 mL) was stirred at 80 °C for 8 h. The
solvent was removed in vacuo and residue was purified by
flash column (silica gel; CH2Cl2:MeOH ) 10:1) to give 171 mg
(51.9%) of 10 as an oil: 1H NMR (CDCl3) δ 7.78-7.75 (m, 4H),
7.67 (dd, 2H, J ) 1.2, 8.1 Hz), 7.48-7.22 (m, 14H), 6.36 (d,
1H, J ) 7.8 Hz), 6.34 (d, 1H, J ) 7.8 Hz), 5.81-5.78 (m, 1H),
5.20-5.17 (m, 1H), 4.19-4.16 (m, 1H), 4.15 (d, 1H, J ) 6.2
Hz), 3.22 (dd, 1H, J ) 3.4, 6.1 Hz), 2.92 (d, 1H, J ) 18.8 Hz),
2.42 (dd, 1H, J ) 3.9, 11.9 Hz), 2.39-2.37 (m, 1H), 2.28 (dt,
1H, J ) 3.6, 12.6 Hz), 2.20 (dd, 1H, J ) 6.1, 18.8 Hz), 1.62 (dt,
1H, J ) 5.1, 12.4 Hz), 1.41-1.38 (m, 1H), 1.03 (s, 9H).
7,8-Dideh ydr o-6-[[(1,1-dim eth yleth yl)diph en ylsilyl]oxy]-
4,5-ep oxy-17-m eth yl-(5r,6r)-m or p h in a n -3-a m in e (11). A
mixture of 10 (150 mg, 0.22 mmol), NH2OH‚HCl (30 mg, 0.43
mmol), NaOAc (92 mg, 1.12 mmol) and MeOH (2 mL) was
stirred at 25 °C for 0.5 h and the solvent was removed on a
rotary evaporator. The residue was dissolved in 50 mL CH2-
Cl2 and the solution was washed with saturated sodium
bicarbonate and dried (Na2SO4) and the solvent removed on
the rotary evaporator. The residue was purified by flash
column (silica gel; CH2Cl2:MeOH ) 12:1) to give 110 mg
(96.5%) of 11 as a foam: 1H NMR (CDCl3) δ 7.84 (d, 2H, J )
7.6 Hz), 7.71 (d, 2H, J ) 7.6 Hz), 7.48-7.37 (m, 6H), 6.50 (d,
1H, J ) 7.8 Hz), 6.43 (d, 1H, J ) 7.8 Hz), 5.77-5.75 (m, 1H),
5.23-5.20 (m, 1H), 4.40 (d, 1H, J ) 6.1 Hz), 4.25-4.22 (m,
1H), 3.49 (s, 2H), 3.27 (dd, 1H, J ) 6.2, 9.4 Hz), 2.98 (d, 1H, J
) 18.3 Hz), 2.51-2.48 (m, 1H), 2.46-2.45 (m, 1H), 2.42-2.37
(m, 1H), 2.40 (s, 3H), 2.26 (dd, 1H, J ) 6.2, 8.6 Hz), 1.76 (dt,
1H, J ) 4.9, 11.8 Hz), 1.74-1.71 (m, 1H); 13C NMR (CDCl3) δ
147.3, 135.7, 135.6, 133.9, 133.6, 133.0, 129.6, 129.6, 129.5,
128.0, 127.5, 124.8, 118.5, 115.9, 91.5, 69.0, 58.7, 46.3, 43.2,
42.9, 40.9, 35.5, 26.7, 20.3, 19.2; MS m/z 523 (MH+).
3-Me t h yla m in o-7,8-d id e h yd r o-4,5-e p oxy-17-m e t h yl-
(5r,6r)-m or p h in a n -6-ol (17). A mixture of 12 (110 mg, 0.2
mmol), TBAF (0.3 mL, 1 M in THF, 0.3 mmol) and THF (3
mL) was stirred at 25 °C for 8 h and the solvent was removed
on a rotary evaporator. The residue was dissolved in CH2Cl2
(50 mL) and the solution was washed with saturated NaHCO3
and dried (Na2SO4). Removal of solvent provided a residue that
was purified by flash column (silica gel; CH2Cl2:MeOH ) 4:1,
then CH2Cl2:MeOH:NH4OH ) 4 mL:1 mL:2 drops) to give 48
mg (78.5%) of 17 as a foam: 1H NMR (CDCl3) δ 6.55 (d, 1H, J
) 7.8 Hz), 6.44 (d, 1H, J ) 7.8 Hz), 5.68-5.65 (m, 1H), 5.30-
5.27 (m, 1H), 4.83 (d, 1H, J ) 7.6 Hz), 4.14 (d, 1H, J ) 6.6
Hz), 3.35 (dd, 1H, J ) 3.2, 5.9 Hz), 3.02 (d, 1H, J ) 18.5 Hz),
2.82 (s, 3H), 2.67-2.66 (m, 1H), 2.59 (dd, 1H, J ) 4.1, 12.0
Hz), 2.48-2.42 (m, 1H), 2.44 (s, 3H), 2.30 (dd, 1H, J ) 6.4,
18.5 Hz), 2.06 (dt, 1H, J ) 5.1, 12.4 Hz), 1.88-1.85 (m, 1H);
13C NMR (CDCl3) δ 145.6, 133.0, 131.6, 128.6, 128.2, 123.3,
119.4, 111.0, 91.0, 66.3, 58.9, 46.4, 42.9, 42.8, 40.7, 35.7, 30.7,
20.1; MS m/z 299 (MH+); [R]D24 ) -90.0° (c ) 0.4, CHCl3). Anal.
(C18H22N2O2‚0.75H2O) C, H, N.
N,N-Dim et h yl-7,8-d id eh yd r o-6-[[(1,1-d im et h ylet h yl)-
d ip h en ylsilyl]oxy]-4,5-ep oxy-17-m eth yl-(5r,6r)-m or p h i-
n a n -3-a m in e (13). A mixture of 9 (300 mg, 0.48 mmol),
Pd(OAc)2 (6 mg, 0.2 mmol), BINAP (17 mg, 0.027 mmol), NaOt-
Bu (64 mg, 0.67 mmol), dimethylamine (0.335 µL, 2 M in THF,
0.67 mmol) and toluene (5 mL) was stirred at 80 °C under N2
in sealed tube for 8 h. The solvent was removed on a rotary
evaporator and the residue was purified by flash column (silica
gel; CH2Cl2:MeOH:NH4OH ) 20 mL:1 mL:2 drops) to give 240
mg (91.2%) of 13 as an oil: 1H NMR (CDCl3) δ 7.82 (d, 2H, J
) 6.8 Hz), 7.68 (d, 2H, J ) 6.8 Hz), 7.47-7.31 (m, 6H), 6.57
(d, 1H, J ) 8.0 Hz), 6.51 (d, 1H, J ) 8.0 Hz), 5.75-5.72 (m,
1H), 5.18 (dt, 1H, J ) 2.7, 9.8 Hz), 4.48 (d, 1H, J ) 6.0 Hz),
4.17-4.14 (m, 1H), 3.25 (dd, 1H, J ) 2.9, 6.1 Hz), 2.99 (d, 1H,
J ) 18.8), 2.91 (s, 6H), 2.49-2.46 (m, 1H), 2.42-2.35 (m, 2H),
2.38 (s, 3H), 2.29 (dd, 1H, J ) 6.4, 18.6 Hz), 1.79-1.72 (m,
2H); MS m/z 551 (MH+).
3-Am in o-7,8-d id eh yd r o-4,5-ep oxy-17-m et h yl-(5r,6r)-
m or p h in a n -6-ol (16). A mixture of 11 (110 mg, 0.21 mmol),
TBAF (0.29 mL, 1 M in THF, 0.29 mmol) and THF (4 mL)
was stirred at 25 °C for 12 h and the solvent was removed on
the rotary evaporator. The residue was dissolved in CH2Cl2,
washed with water, dried (Na2SO4), and the solvent was
removed on the rotary evaporator. The residue was purified
with flash column (silica gel; CH2Cl2:MeOH ) 4:1, then CH2-
Cl2:MeOH:NH4OH ) 4 mL:1 mL:4 drops) to give 50 mg (83.3%)
of 16: mp ) 193-195 °C; 1H NMR (CDCl3) δ 6.47 (d, 1H, J )
8.0 Hz), 6.45 (d, 1H, J ) 8.0 Hz), 5.70-5.68 (m, 1H), 5.30-
5.27 (m, 1H), 4.84 (d, 1H, J ) 6.3 Hz), 4.15 (dd, 1H, J ) 2.4,
6.3 Hz), 4.16-4.14 (m, 1H), 3.6 (s, 3H, broad), 3.33 (dd, 1H, J
) 3.1, 5.8 Hz), 2.30 (d, 1H, J ) 18.5 Hz), 2.64 (t, 1H, J ) 2.4
Hz), 2.58 (dd, 1H, J ) 4.2, 12.2 Hz), 2.44-2.39 (m, 1H), 2.27
(dd, 1H, J ) 6.3, 18.5 Hz), 2.04 (dt, 1H, J 5.1, 12.5 Hz), 1.87-
1.84 (m, 1H); 13C NMR (CDCl3) δ 146.2, 133.0, 129.7, 128.3,
127.2, 125.2, 119.3, 116.2, 91.0, 66.3, 58.7, 46.3, 42.9, 42.8, 40.7,
3-Dim eth yla m in o-7,8-d id eh yd r o-4,5-ep oxy-17-m eth yl-
(5r,6r)-m or p h in a n -6-ol (18). A mixture of 13 (200 mg, 0.64
mmol), TBAF (0.96 µL, 1 M in THF, 0.96 mmol) and THF (5
mL) was stirred at 25 °C for 6 h. The solvent was removed on
a rotary evaporator and the residue was purified by prepara-
tive TLC (silica gel; CH2Cl2:MeOH ) 3:1) to give 90 mg (79.6%)
of 18 as a foam: 1H NMR (CDCl3) δ 6.56 (d, 1H, J ) 8.3 Hz),
6.54 (d, 1H, J ) 8.3 Hz), 5.71-5.68 (m, 1H), 5.29 (dt, 1H, J )
2.7, 8.8 Hz), 4.83 (d, 1H, J ) 8.6 Hz), 4.16-4.14 (m, 1H), 3.34
(dd, 1H, J ) 3.2, 6.1 Hz), 3.04 (d, 1H, J ) 18.5 Hz), 2.80 (s,
6H), 2.66-2.65 (m, 1H), 2.59 (dd, 1H, J ) 4.4, 12.2 Hz), 2.44
(s, 3H), 2.43 (dt, 1H, J ) 3.7, 12.5 Hz), 2.32 (dd, 1H, J ) 6.4,
18.6 Hz), 2.04 (dt, 1H, J ) 4.9, 12.4 Hz), 1.89-1.86 (m, 1H);
13C NMR (CDCl3) δ 148.8, 134.5, 133.2, 129.9, 128.1, 126.3,
119.3, 115.3, 90.4, 66.4, 58.6, 46.3, 42.9, 42.4, 42.0, 40.6, 35.8,
20.3; MS m/z 313 (MH+); [R]D ) -100.0° (c ) 0.71, CHCl3).
24
Anal. (C19H24N2O2‚0.75H2O) C, H, N.
N-P h en yl-7,8-d id eh yd r o-6-[[(1,1-d im eth yleth yl)d ip h e-
n ylsilyl]oxy]-4,5-ep oxy-17-m eth yl-(5r,6r)-m or p h in a n -3-
a m in e (14). A mixture of 9 (300 mg, 0.48 mmol), Pd2 (dba)3
(22 mg, 0.024 mmol), DPPF (40 mg, 0.072 mmol), NaOt-Bu
(55 mg, 0.576 mmol), aniline (82 µL, 0.90 mmol) and toluene
(5 mL) was stirred at 80 °C for 5 h. The reaction mixture was
passed through a short silica gel plug (eluent CH2Cl2:MeOH
) 10:1) and the solvent was removed. The residue was purified
by flash column (silica gel; CH2Cl2:MeOH ) 5:0.2) to give 80
mg (62.9%) of 14 as an oil: 1NMR (CDCl3) δ 7.85 (d, 2H, J )
6.9 Hz), 7.76 (d, 2H, J ) 6.9 Hz). 7.51-7.40 (m, 5H, 7.30 (t,
2H, J ) 7.9 Hz), 7.10 (d, 1H, J ) 8.0 Hz), 7.08 (d, 2H, J )
24
35.6, 20.2; MS m/z 285 (MH+); [R]D ) -130.3° (c ) 0.54,
CHCl3). Anal. (C17H20N2O2‚0.25H2O) C, H, N.
N-Meth yl-7,8-d id eh yd r o-6-[[(1,1-d im eth yleth yl)d ip h e-
n ylsilyl]oxy]-4,5-ep oxy-17-m eth yl-(5r,6r)-m or p h in a n -3-
a m in e (12). A mixture of 9 (500 mg, 0.8 mmol), DPPF (66
mg, 0.12 mmol), Pd2(dba)3 (37 mg, 0.04 mmol), NaOt-Bu (92
mg, 0.96 mmol), CH3NH2 (0.8 mL, 2 M in THF, 1.6 mmol) and
toluene (10 mL) was stirred at 80 °C for 15 h and the solvent
was removed on the rotary evaporator. The residue was
purified by flash column (silica gel; CH2Cl2:MeOH ) 12:1) to
give 110 mg (25.7%) of 12 as a foam: 1H NMR (CDCl3) δ 7.78

3564 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 19
Wentland et al.
12.4 Hz), 6.92 (t, 1H, J ) 7.0 Hz), 6.58 (d, 1H, J ) 8.1 Hz),
5.84-5.82 (m, 1H), 5.67 (s, br, 1H, D2O), 5.30 (dt, 1H, J ) 2.4,
9.8 Hz), 4.46 (d, 1H, J ) 6.1 Hz), 4.33-4.31 (m, 1H), 3.35 (dd,
1H, J ) 3.2, 6.1 Hz), 3.08 (d, 1H, J ) 18.5 Hz), 2.58-2.53 (m,
2H), 2.50-2.42 (m, 1H), 2.46 (s, 3H), 2.36 (dd, 1H, J ) 6.1,
8.6 Hz), 1.84-1.78 (m, 2H); MS m/z 599 (MH+).
Samples incubated with [3H]naltrindole also contained 10 µM
MgCl2 and 0.5 mM phenylmethanesulfonyl fluoride. Nonspe-
cific binding was measured by inclusion of 10 µM naloxone.
The binding was terminated by filtering the samples through
Schleicher & Schuell no. 32 glass fiber filters using a Brandel
48-well cell harvester. The filters were subsequently washed
three times with 3 mL of cold 50 mM Tris-HCl, pH 7.5, and
were counted in 2 mL Ecoscint A scintillation fluid. For [3H]-
naltrindole and [3H]U69,593 binding, the filters were soaked
in 0.1% poly(ethylenimine) for at least 60 min before use. IC50
values were be calculated by least-squares fit to a logarithm-
probit analysis. Ki values of unlabeled compounds were
calculated from the equation: Ki ) (IC50)/1 + S where S )
(concentration of radioligand)/(Kd of radioligand).34 Data are
the mean ( SE from at least three experiments performed in
triplicate.
Ad en ylyl Cycla se Assa ys. Methods for the quantification
of cyclic AMP production in SH-SY5Y membranes were
measured as described previously.35 Membranes, 50 µg of
proteins in a homogenizing buffer (40 mM HEPES-Na+, 2 mM
EGTA, 0.32 M sucrose, pH 7.4), were incubated for 15 min in
a 30 °C water bath with 10 µM either DAMGO, a µ-selective
ligand, or the aminomorphine derivatives, and in the presence
of 20 mM HEPES, pH 7.4, 30 U creatine phosphokinase, 20
mM phosphocreatine, 1 mM phenanthroline, 60 µM isobutyl-
methylxanthine, 0.1 mM GTP and 0.1 mM ATP. The reaction
was stopped by the addition of 4.5% perchloric acid and
neutralized with 30% KHO3. After centrifugation at 14000g,
for 4 min, 100 µL of supernatant were used to determine cyclic
AMP accumulation, using a [3H]cyclic AMP assay kit (Diag-
nostic Products Corp., Los Angeles, CA). Results are reported
as the mean percent inhibition of basal activity (in the absence
of agonist) ( SE. Each experiment was performed in duplicate
and each experiment was repeated at least three times.
3-P h en yla m in o-7,8-d id eh yd r o-4,5-ep oxy-17-m et h yl-
(5r,6r)-m or p h in a n -6-ol (19). A mixture of 14 (80 mg, 0.13
mmol), TBAF (0.174 µL, 1 M in THF, 0.174 mmol) and THF
(1 mL) was stirred at 25 °C for 3 h and the solvent was
removed. The residue was dissolved in CH2Cl2 (20 mL) and
washed with water (20 mL) and brine (20 mL). The CH2Cl2
layer was dried (Na2SO4) and concentrated using a rotary
evaporator to give a residue that was purified by flash
chromatography (silica gel; CH2Cl2:MeOH:NH4OH ) 5 mL:1
mL:3 drops) to give 40 mg (83.1%) of 19 as a foam: 1H NMR
(CDCl3) δ 7.24 (t, 1H, J ) 8.0 Hz), 6.94 (d, 1H, J ) 8.0 Hz),
6.87-6.84 (m, 2H), 6.59 (d, 1H, J ) 8.0 Hz)5.74-5.70 (m, 1H),
5.48 (s, 1H, D2O), 5.35 (dt, 1h, J ) 2.4, 10.0 Hz), 4.87 (d, 1H,
J ) 6.6 Hz), 4.17-4.16 (m,1H), 3.38 (dd, 1H, J ) 3.2, 7.0 Hz),
3.18 (d, 1H, J ) 18.8 Hz), 2.69-2.66 (m, 1H), 2.61 (dd, 1H, J
) 3.9, 12.2 Hz), 2.46 (s, 3H), 2.45 (dt, 1H, J ) 3.6, 8.3 Hz),
2.33 (dd, 1H, J ) 6.4, 18.6 Hz), 2.08 (dt, 1H, J ) 5.4, 12.7 Hz),
24
1.90-1.88 (m, 1H).; MS m/z 361 (MH+); [R]D ) -125.0° (c )
0.75, CHCl3). Anal. (C23H24N2O2‚0.75H2O).
N-P h en ylm eth yla m in o-7,8-d id eh yd r o-6-[[(1,1-d im eth -
ylet h yl)d ip h en ylsilyl]oxy]-4,5-ep oxy-17-m et h yl-(5r,6r)-
m or p h in a n -3-a m in e (15). A mixture of 9 (300 mg, 0.48
mmol), BINAP (18 mg, 0.029 mmol), Pd(OAc)2 (6.3 mg, 0.028
mmol), NaOt-Bu (63 mg, 0.58 mmol), benzylamine (66 mg, 0.58
mmol) and toluene (6 mL) was stirred at 80 °C for 8 h under
N2. The solvent was removed and the resulting residue was
purified by flash chromatography (silica gel; CH2Cl2:MeOH )
12:1) to give 245 mg (83.6%) of 15 as an oil: 1H NMR (CDCl3)
δ 7.78 (d, 2H, J ) 7.9 Hz), 7.68 (d, 2H, J ) 7.9 Hz), 7.64-7.22
(m, 11H), 5.75 (d, 1H, J ) 8.7 Hz), 5.19 (d, 1H, J ) 9.8 Hz),
4.38-4.36 (m, 2H), 4.22-4.20 (m, 1H), 3.89 (s, 1H, D2O
exchange), 3.23 (dd, 1H, J ) 3.0, 5.4 Hz), 2.95 (d, 1H, J )
18.6 Hz), 2.46-2.37 (m, 3H), 2.42 (s, 2H), 2.23 (dd, 1H, J )
6.1, 8.3 Hz), 1.77-1.71 (m, 2H); 13C NMR (CDCl3) δ 146.9,
139.7, 135.6, 133.8, 133.6, 133.0, 130.6, 129.6, 129.6, 128.8,
128.3, 128.1, 127.5, 127.4, 127.4, 126.8, 123.6, 118.5, 111.5,
91.5, 69.0, 58.8, 48.5, 46.3, 43.3, 42.9, 40.9, 35.5, 26.7, 20.1,
19.2.
Ack n ow led gm en t. We gratefully acknowledge the
discussions with the late Professors Sydney Archer and
Arthur G. Schultz of Rensselaer and also those with
Professor Frank Hauser (University at Albany). Also
acknowledged are the contributions of the following
Rensselaer chemists: Mr. Christopher Cioffi, Ms. Ying-
chun Ye, and Dr. Qun Zhou. Funding of this research
was from NIDA (DA01674, DA03742, DA12180, and
KO5-DA00360).
3-P h e n ylm e t h yla m in o-7,8-d id e h yd r o-4,5-e p oxy-17-
m eth yl-(5r,6r)-m or p h in a n -6-ol (20). A mixture of 15 (136
mg, 0.22 mmol), TBAF (0.33 mL, 1 M in THF, 0.33 mmol) and
THF (3 mL) was stirred at 25 °C for 8 h. After removal of the
solvent, the residue was dissolved in CH2Cl2 (50 mL). The
solution was washed with saturated sodium bicarbonate (30
mL), dried (Na2SO4) and concentrated to give a residue that
was purified by preparative TLC (silica gel; CH2Cl2:MeOH:
NH4OH ) 5 mL:1 mL:2 drops) to give 80 mg of (96.3%) 20 as
a foam: 1H NMR (CDCl3) δ 7.33-7.23 (m, 5H), 6.47 (d, 1H, J
) 7.8 Hz), 6.41 (d, 1H, J ) 7.8 Hz), 5.64 (m, 1H), 5.25 (dt, 1H,
J ) 2.6, 10 Hz), 4.75 (d, 1H, J ) 6.3 Hz), 4.26 (s, 2H), 4.06 (m,
1H), 3.33 (dd, 1H, J ) 3.2, 6.1 Hz), 2.30 (d, 1H, J ) 18.8 Hz),
2.64 (t, 1H, J ) 2.7 Hz), 2.57 (dd, 1H, J ) 3.9, 11.9 Hz), 2.46-
2.40 (m, 1H), 2.43 (s, 3H), 2.27 (dd, 1H, J ) 6.3, 18.6 Hz), 2.02
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