The power of visual imagery in drug design. Isopavines as a new class of morphinomimetics and their human opioid receptor binding activity

Article abstract of DOI:10.1021/jm020164l

The importance of visual imagery and relational thinking manifests itself in a heuristic approach to the design and synthesis of potential morphinomimetics as agonists of the human-receptor. The well-known class of alkaloids represented by the isopavine n

Full text of DOI:10.1021/jm020164l

34
J . Med. Chem. 2003, 46, 34-48
Th e P ow er of Visu a l Im a ger y in Dr u g Design . Isop a vin es a s a New Cla ss of
Mor p h in om im etics a n d Th eir Hu m a n Op ioid Recep tor Bin d in g Activity†
Stephen Hanessian,* Saravanan Parthasarathy, and Marc Mauduit
Department of Chemistry, Universite´ de Montre´al, C.P. 6128, Succursale Centre-Ville, Montre´al, Que´bec H3C 3J 7, Canada
Kemal Payza
Molecular Pharmacology Section, AstraZeneca, R&D Montreal, 7171 Frederick-Banting, St-Laurent, Quebec, Canada H4S 1Z9
Received April 18, 2002
The importance of visual imagery and relational thinking manifests itself in a heuristic approach
to the design and synthesis of potential morphinomimetics as agonists of the human µ-receptor.
The well-known class of alkaloids represented by the isopavine nucleus has a topological
resemblance to the morphine skeleton, especially when viewed in a particular way. Enantiopure
isopavines can be readily obtained from a 1,2 Stevens rearrangement of 13-substituted
dihydromethanodibenzoazocines, prepared in four steps from D- and L-amino acids. Consider-
ation of the topology and the expected orientation of the nitrogen lone pair for a better overlap
with morphine necessitates the utilization of D-amino acids. By variation of the substituents
on the aromatic rings and a judicious choice of ring substituents, it is possible to obtain low
nanomolar binding to the human µ receptor while maintaining good to excellent µ/δ selectivity.
Agonist-like activity is indicated in a functional assay for one of the analogues originally derived
from D-alanine as a precursor. X-ray crystal structures of several compounds corroborate
stereochemistries and overall topologies.
In tr od u ction
the synthesis of peptide24-26 and non-peptide ana-
logues27 have relied on these principles during the
recent past.
The potent analgesic properties of morphine, a promi-
nent constituent of the opiate class of alkaloids, has been
recognized since the time of Helen of Troy.1 Consider-
ably more potent than its close analogue codeine, it is
used in a hospital environment for temporary alleviation
of extreme pain associated with a host of disease
conditions. Morphine is one of the most widely investi-
gated natural products, with a rich history in chemistry
and pharmacology.2-4
The analgesic properties of opioids are now better
understood in the context of their interaction with three
major types of receptors, namely, δ, κ, and µ,5 which
belong to the G-protein-coupled receptor superfamily.6
Although X-ray structural data are still unavailable for
these receptors, several studies proposing three-dimen-
sional models using computational methods have been
reported over the years.7-11 The identification of specific
amino acid sequences in the cloned receptors5,12,13 has
greatly expanded the understanding of ligand-receptor
interactions, offering insights into the molecular deter-
minants for effective binding.14 While specific details are
still elusive, it is generally accepted that morphine and
its congeners interact with the δ, κ, and µ receptors on
the basis of a three-dimensional pharmacophore model
that involves four sites, namely, a protonated amine,
two (or three) hydrophobic groups, and an H-bond donor
to a complementary site.14-19 Indeed, numerous efforts
concerned with the synthesis of analogues,20 the chemi-
cal modification of the natural opioid alkaloids,21-23 and
In view of the nonspecific recognition of the opioid
receptors, morphine and many of its congeners have
serious side effects such as physical dependence, respi-
ratory depression, and muscle rigidity.28-31 Strategies
that capitalize on different levels of agonist efficacy vis-
a`-vis these receptors have been advocated as a means
of diminishing side effects.14 A large proportion of opioid
ligands have centered around the 4,5-epoxymorphinan,
dihydromorphone, and dihydromorphindole structures.32
Morphine, nalorphine, naltrexone, natrindole, oxymor-
phindole, and their variants are representative opioids
that belong to these classes. Tricyclic structures have
included morphinans, benzomorphans, aminotetralins,
and cyclazocines, to mention a few. The cyclazocines
have received considerable attention as clinical candi-
dates in the early 1970s33,34 and continue to be interest-
ing pharmacological probes for the functional require-
ments of the opioid receptors.35 For historical reasons,36
peptidic compounds have also been pursued as a back-
drop to non-peptidic counterparts.24,37,38
Major advances in identifying receptor subtypes and
pharmacophore recognition sites through site-directed
mutagenesis and other structural tools have provided
convincing biochemical evidence for the existence of
homo- and heterodimers among opioid receptors.39 For
example, “message” and “address” sequences40 have
been identified and morphinan structures synthesized
as probes for heterodimeric δ, κ, and µ recognition
sites.41,42 Perhaps one of the more intriguing conse-
quences of these studies was the synthesis of a C2
centrosymmetric “dimeric” morphine analogue, norbin-
† Dedicated to Professor Philip Portoghese for his seminal contribu-
tions to the chemistry of opioids.
* To whom correspondence should be addressed. Fax: (514) 343-
5728. Phone: (514) 343-6738. E-mail: stephen.hanessian@umontreal.ca.
10.1021/jm020164l CCC: $25.00 © 2003 American Chemical Society
Published on Web 11/27/2002

Isopavines
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 1 35
Sch em e 1a
F igu r e 1. Morphine and isopavine perspectives.
altrophimine (BNI).43 Further studies revealed that half
of the dimer served as a scaffold to rigidly hold the basic
nitrogen in a favorable position to interact with one of
the receptors.44-46 While rigid structures such as mor-
phine itself are not absolute requirements for favorable
binding, the proper alignment of pharmacophores and
the all too important orientation of the nitrogen lone
pair47,48 are critical. Fentanyl, containing a piperidine
moiety, represents an example of a “flexible” monocyclic
opioid receptor ligand with considerable history.16
a
(i) 4-(X)-Benzyl bromide, NaHCO3, THF/DMSO, reflux, (ii)
LAH, THF, 0 °C to room temp, (iii) (COCl)2, DMSO, Et3N, CH2Cl2,
-78 °C, (iv) AlCl3, CH2Cl2, 0 °C to room temp, (v) RX, acetone,
reflux, (vi) t-BuOK, dioxane, 80 °C, (vii) aqueous HBr, reflux, (viii)
Ac2O, Et3N, CH2Cl2, (ix) BINAP, Pd(dba)3, t-BuONa, R′R′′NH, or
R′′NH2, toluene, 80 °C. #Cyclopropylmethyl.
1,2 Stevens rearrangement54,55 of the corresponding 13-
substituted dihydromethanodibenzoazocines.52 The lat-
ter compounds were in turn prepared from the appro-
priate N,N-dibenzylamino aldehydes (derived from the
corresponding amino acids)56 by a two-stage intramo-
lecular Friedel-Crafts reaction. Symmetrical unsubsti-
tuted dihydromethanodibenzoazocines have been known
for some time,57,58 but their desymmetrized enantiopure
analogues were not previously described. Their phar-
macological properties have remained largely unex-
plored.59
Scheme 1 illustrates the synthesis of dihydrometha-
nodibenzoazocines 6a -c from D-alanine with variations
in the benzyl substituent. Treatment with methyl iodide
or cyclopropylmethyl iodide in refluxing acetone afforded
the corresponding N-methyl or N-cyclopropylmethyl
quaternary salts, which were subjected to rearrange-
ment in the presence of t-BuOK in refluxing dioxane.60
The corresponding isopavines 7a -c and 8a -c were
obtained in good to excellent yields. The methoxy groups
were cleaved with aqueous HBr at reflux temperature61
to afford the free bis-phenols 9 and 10. Acetylation led
to 11 and 12, which are formally related to heroin by
analogy with the diacetylmorphine structure as shown
in Figure 1.
Mor p h in om im etic Design th r ou gh Visu a l
Im a ger y
The power of visual association especially in a three-
dimensional sense is an ongoing challenge in our daily
encounters with molecular entities.49 Much like eye-
teasing Dalie`sque paintings of motifs that are “the same
and not the same,50 the surrealism of molecular simi-
larities and of pharmacophore juxtapositions can be just
as intriguing. The isopavines, readily available from the
corresponding dihydromethanodibenzoazocines (see
below),51-53 represent examples of rigid molecules, with
exquisitely deployed topology and functionality an-
chored around a tertiary nitrogen atom originally
derived from a natural amino acid. Thus, the isopavine
prepared from D-alanine is shown in two perspective
drawings represented by A and A′ (Figure 1). At first
glance, the topological resemblance of isopavine A to
morphine 1 is not obvious. However, a view in another
perspective such as A′ (2) reveals a skeletal convergence
with morphine, where some of the desired pharmacoph-
oric elements that are required for µ opioid receptor
binding and activation are present. Likewise, the enan-
tiomeric isopavine, ent.A (or A′, 4) derived from L-
alanine,51,52 is topologically related to the enantiomer
of morphine 3, which is 100 times less active than the
natural product. The perspective-based design and
synthesis of isopavines and the choice of a D- rather than
an L-amino acid51 as a preferred chiral progenitor to
achieve potential morphine-like receptor binding activ-
ity are the objectives of this paper.
The p-bromoarylisopavines were transformed to the
corresponding bis-N-alkyl and bis-N-phenyl analogues
13-19 by versatile Pd-catalyzed insertion reactions of
appropriate substituted amines.62 Scheme 2 shows the
oxidative demethylation63 of 7a to yield the correspond-
ing des-N-methyl analogue 20. Allylation, benzylation,
and acetylation afforded the respective N-substituted
compounds 21-23.
Syn th esis
Unlike the dihydromethanodibenzoazocines, there are
numerous natural products belonging to the isopavine
group of alkaloids.53,64 O-Methylthalisopavine, 26c, has
The general protocol for the synthesis of p-aryl-
substituted isopavines involved a highly stereocontrolled

36 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 1
Hanessian et al.
Sch em e 2a
Sch em e 4a
a
(i) Pd-C, MeOH, Air, (iia) RX, Na2CO3, THF, reflux, or (iib)
Ac2O, Et3N, CH2Cl2, room temp.
Sch em e 3a
a
(i) 4-(X)-Benzyl bromide, NaHCO3, THF/DMSO, reflux, (ii)
LAH, THF, 0 °C to room temp, (iii) PivCl, Et3N, CH2Cl2, -10 to 0
°C, (iv) (COCl)2, DMSO, Et3N, CH2Cl2, -78 °C, (v) AlCl3, CH2Cl2,
0 °C to room temp, (vi) DIBALH, toluene, -78 °C, (vii) SOCl2,
benzene, reflux, (viii) t-BuOK, dioxane, 80 °C, (ix) BINAP, Pd-
(dba)3, t-BuONa, R′R′′NH, toluene, 80 °C, (x) aqueous HBr, reflux,
(xi) Ac2O, Et3N, CH2Cl2.
a
(i) (3,4)-Dimethoxybenzyl bromide, NaHCO3, THF/DMSO,
the aryl-substituted dihydromethanodibenzoazocines
29a -d . Intramolecular quaternization via the chlorides
31a -d followed by Stevens rearrangement led to the
bridged tricyclic isopavines 32a -d , respectively. Pd-
catalyzed insertion62 of amines into the dibromo ana-
logue 32c took place only partially to afford the monoben-
zylamino derivative 33 (or its alternative isomer in
which the aromatic substituents are interchanged).
Treatment of 32b with aqueous HBr at reflux afforded
the corresponding bis-phenolic analogue 34a , which was
converted to the diacetate 34b. The stereochemical
course of the Stevens rearrangement to give the ex-
pected isopavines was corroborated by a single-crystal
X-ray analysis of the difluoro analogue 32d (Scheme 4).
The tetracyclic fused piperidine analogue 39 was syn-
thesized according to the protocol shown in Scheme 5
and proceeding via the 13-hydroxypropyldihydrometha-
nodibenzoazocine 38. Selected isopavine analogues were
also prepared starting from L-amino acids using the
same methods described for the D-enantiomer.
reflux, (ii) LAH, THF, 0 °C to room temp, (iii) (COCl)2, DMSO,
Et3N, CH2Cl2, -78 °C, (iv) AlCl3, CH2Cl2, 0 °C to room temp, (v)
RX, acetone, reflux, (vi) t-BuOK, dioxane, 80 °C.
been synthesized in enantiomerically pure form by two
groups65,66 and in racemic form also.67 A 13-methyl ent-
O-methylthalisopavine 26a and its N-cyclopropylmethyl
analogue 26b were prepared by the same methodology
described above as shown in Scheme 3.
The importance of the proper orientation of the
nitrogen lone pair in the isopavine series was recognized
when we compared the µ receptor binding affinities52
of a constrained tricyclic isopavine, with a similar
analogue derived from L-alanine (Figure 1, ent.A/A′).
The synthetic sequence for the tricyclic analogues in this
series is shown in Scheme 4, which starts with the
chemoselective modification of L-glutamic acid to afford
the N,N-dibenzyl-2-aminopentane-1,5-diol monopiv-
aloate analogues 28a -d . Oxidation to the corresponding
aldehyde and Friedel-Crafts cyclization proved to be
successful (especially utilizing a pivaloate ester) to give

Isopavines
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 1 37
Sch em e 5a
differentiate the two pathways leading to isopavines A
and B in the D-alanine series, the starting dihy-
dromethanodibenzoazocines must carry different sub-
stituents on the aryl portion.51,52
In Vitr o Recep tor Bin d in g Affin ities
In vitro binding affinities of the synthetic isopavines
were determined with the use of cloned human δ, κ, and
µ opioid receptors.69 The IC50 values and selectivities
for the bridged bicyclic isopavines derived from D-
alanine and for the bridged tricyclic isopavines derived
from L-glutamic and 2-aminoadipic acids are listed in
Table 1.
Our original design principle relied on a topological
and functional convergence with morphine itself while
maintaining a favorable orientation of the nitrogen lone
pair in the synthetic compounds. Those analogues in
which the phenyl rings were unsubstituted in the 7a
and 8a series exhibited 200-100 nM binding affinity
to the µ receptor with no activity at δ or κ receptors
(Table 1, entries 4 and 5).
a
(i) Benzyl bromide, NaHCO3, THF/DMSO, reflux, (ii) LAH,
THF, 0 °C to room temp, (iii) PivCl, Et3N, CH2Cl2, -10 to 0 °C,
(iv) (COCl)2, DMSO, Et3N, CH2Cl2, -78 °C, (v) AlCl3, CH2Cl2, 0
°C to room temp, (vi) DIBALH, toluene, -78 °C, (vii) SOCl2,
benzene, reflux, (viii) t-BuOK, dioxane, 80 °C.
Introduction of p-bromo or p-methoxy groups in the
phenyl rings resulted in compounds that retained the
µ binding and selectivity (Table 1, entries 10-13).
However, the bis-phenolic analogues 9 and 10 (Table
1, entries 14 and 15) showed a significant improvement
in binding with IC50 values of 16 and 6.4 nM, respec-
tively. The δ and κ binding was also improved compared
to the analogues described above. The corresponding bis-
phenolic acetates 11 and 12 (Table 1, entries 16 and
17) maintained the same trend, with the N-cyclopropy-
lmethyl analogues being about 3-5 times more active
than the N-methyl analogues.
The introduction of amino groups in cyclazocines has
proven to be beneficial for µ and κ receptor binding.35
In this regard the bis-aminophenyl analogues 14 and
18 (Table 1, entries 18 and 19) had higher affinity for
the µ and δ receptors than for κ. Low nanomolar µ
binding was observed for the bis-aminobenzyl analogues
13 and 17, with the former being approximately 2 and
20 times as selective vs δ and κ, respectively. Changing
the phenyl substituent to bis-N-methylpiperazine in the
N-methyl and N-cyclopropylmethyl series (compounds
15, 19, Table 1, entries 22 and 23) resulted in a lower
affinity of µ receptor binding compared to the corre-
sponding bis-N-aminobenzyl analogues 13 and 17.
Removal of the N-methyl or N-cyclopropylmethyl group
as in the case of the secondary amine analogue 20
retained selectivity; i.e., the resulting compound still
had no detectable binding to δ and κ (Table 1, entry 6).
As previously mentioned, we had surmised that
introduction of a third ring such as in the bridged
tricyclic analogue 32a would nicely converge with the
morphine skeleton.51 The rigidity of the ring system
would also place the nitrogen lone pair in a favorable
orientation. This topology could only be accessible from
L-amino acids precursors via cyclic quaternary salts. We
were indeed pleased that 32a 51 showed an IC50 of 59
nM toward the µ opioid receptor with excellent selectiv-
ity toward the δ and κ receptors (Table 1, entry 27). The
piperidine analogue 39 maintained the selectivity but
showed lower affinity for the µ opioid receptor (Table 1,
entry 28). Bis-bromo, bis-methoxy, and bis-fluoro (X-ray
crystal structure) analogues 32b -d (Table 1, entries
F igu r e 2. Proposed pathway for [1,2] Stevens rearrangement.
Mech a n istic Issu es
Before presentation of the receptor binding activities
of the isopavines, it is of interest to discuss the stere-
ochemical issues related to the Stevens rearrangement
as illustrated in Figure 2. Abstraction of one of the
diastereotopic C-5 benzylic protons from the dihy-
dromethanodibenzoazocinium iodide A leads to ylid A,
then to iminium ion A′ (or its diradical equivalent).68
Intramolecular closure via a C-7 attack affords isopavine
A, which is the observed diastereomer as confirmed by
X-ray crystallography.51 Alternatively, abstraction of a
C-7 benzylic proton will lead to ylid B and to iminium
ion B′ (or its diradical equivalent). Ring closure via a
C-5 attack leading to the isopavine B is apparently not
favored. On the other hand, the tricyclic iminium ion
resulting from 31a -d (Scheme 4) via intramolecular
alkylation will cyclize via a preferred pathway that leads
to a type B isopavine (where a pyrrolidine ring is
appended).51 Thus, to achieve the desired topological
convergence and nitrogen lone pair orientation with
morphine, one must use D-amino acids to access the
bridged isopavines of type A via N-methylation. To

38 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 1
Hanessian et al.
Ta ble 1. Binding Affinities of Synthetic Isopavines for the Human Opioid Receptors
µ
Hδ
Hκ
Hµ
nM
selectivity
a
a
a
entry
compd
R
X
IC50
,
nM
150
5.1 0.4
>9300 9335 to
>10000
SEMb
IC50
,
nM
170
4.0 0.2
SEMb
IC50
,
SEMb
vs δ (-fold)c
1
2
3
(-)-morphine Me
OH
OH
OMe
13
35
0.57 0.10
0.13 0.03
265
39
>89
levorphanol
codeine
Me
Me
15000
2000
105
20
4
7a
Me
H
>10000
>7500
7500 to
230
19
>43
>10000
5
6
7
8a
20
21
CPMd
H
allyl
H
H
H
>10000
>10000
>9700
>10000
>10000
>4000
1080
650
78
81
>9.3
>15
>5
9700 to
>10000
8900 to
>10000
4000 to
>10000
5800 to
>10000
2000
190
8
9
22
23
benzyl
acetyl
H
H
>8800
>5800
>10000
>9500
NA
NA
>10000
>10000
9500 to
>10000
10
11
7c
8c
Me
CPM
Br
Br
8840
>10000
500
6920
>4900
864
4900 to
360
2050
130
72
25
>5
>10000
12
13
14
15
16
7b
8b
9
10
11
Me
CPM
Me
CPM
Me
OMe
OMe
OH
OH
OAc
>10000
6630
>10000
5330
961
420
1030
16
96
190
2
NA
6.4
80
1190
110
1220
18
1300
460
>4700
55
4700 to
204
>9500
20
9500 to
6.4 1.4
72
>23
200
44
>10000
>10000
17
18
19
20
21
22
23
24
25
26
27
12
14
18
13
17
15
19
16
CPM
Me
CPM
Me
CPM
Me
CPM
Me
OAc
3300
530
890
120
49
740
55
65
12
6
300
120
520
2020
3600
1200
640
31
460
470
190
77
2
400
360
44
10
74
9.5
11
15
7.0
47
3.0
11
NA
NA
>131
NHPh
NHPh
NHBn
NHBn
N-Me piperazine
N-Me piperazine
morpholine
OMe
56
13
82
8
7
14
1.5
1.6
14
2500
2040
7500
>10000
>10000
>7800
3200
1600
53
690
690
200
170
>10000
>10000
>10000
6100
26a
26b
32a
Me
CPM
-(CH2)3-
>10000
>10000
59
OMe
H
7800 to
260
12
>10000
28
29
30
31
39
-(CH2)4-
H
>10000
5020
4040
>10000
7400
7400
>10000
>6400
1100
1800
390
500
160
103
130
110
32
>25
10
25
32b
32c
32d
-(CH2)3- Br
470
380
-(CH2)3- OMe
-(CH2)3-
F
6400 to
6
>97
>10000
32
33
34a
34b
-(CH2)3- OH
-(CH2)3- OAc
3800
2900
400
550
7200
>6000
740
6000 to
130
220
37
70
29
13
>10000
34
33
-(CH2)3- Br, NHBne
5300
340
7000
1000
120
5
44
a
b
IC50 values represent the arithmetic mean of 3-10 determinations except for compounds 7a and 8a . Standard error of the mean.
Blank SEM indicates all replicates were >10000. Range is shown instead of SEM if one or more value is >10000. c µ selectivity calculated
as δ IC50/µ IC50. NA indicates insufficient binding potency at µ to obtain a selectivity value. CPM ) cyclopropylmethyl. e Specific location
of 4-aryl substituent not known.
d
29-31) maintained the same selectivity trend with
small variations. The significant improvement in µ
receptor binding in the bis-phenol bridged bicyclic series
9 compared to 7a (and 10 compared to 8a ) can be
intuitively ascribed to a closer relationship to morphine
(Figure 1, isopavine A or A′, X ) H, OH). The binding
affinity is of the order that would be expected theoreti-
cally for an additional dipolar H-bond interaction.70 We
were, however, surprised that the binding of bis-
phenolic analogue 34a to the µ receptor was not
improved compared to the unsubstituted precursor 32a .
An IC50 of 130 nM for the µ receptor is the same as those
for the corresponding bis-methoxy and bis-fluoro ana-
logues (Table 1, entries 30-32). The bis-acetate 34b,
like its bis-phenolic precursor 34a , lost some µ/δ selec-
tivity compared to the bis-fluoro analogue (Table 1,
entry 33). Finally, a mixed p-bromophenyl, p-aminoben-
zyl analogue 33 showed significant µ-receptor binding
at IC50 ) 120 nM, with 44- and 58-fold selectivity versus
δ and κ receptors (Table 1, entry 34). We cannot
ascertain if the para substituents are as shown in 33
or if they are interchanged. A perspective drawing of

Isopavines
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 1 39
Ta ble 2. Binding Affinities of Synthetic Isopavines from L-Alanine for the Human Opioid Receptors
Hδ
hκ
Hµ
nM
µ selectivity
vs δ (-fold)c
a
a
a
entry compd
R
X
IC50
,
nM
SEMb
IC50
,
nM
SEMb
IC50
,
SEMb
28
1
2
3
4
5
6
7
8
40a
40b
40c
40d
40e
40f
Me
H
H
H
H
H
H
H
>10000
>10000
>8700
3442
>10000
>10000
>10000
>5700
>10000
3410
611
695
1010
1050
404
>16
>14
>8.6
3.3
>25
>13
>8.7
NA
i-Pr
i-Bu
Bn
CH2OH
(CH2)2OH
(CH2)3OH
Me
264
500
190
60
8700 to >10000
273
2970
1710
>10000
>9960
>10000
>10000
153
100
14
77
91
9965 to >10000
764
1150
40 g
40h
OMe
5700 to >10000
>10000
a
b
IC50 values represent the arithmetic mean of 3-5 determinations. Standard error of the mean. Blank SEM indicates all replicates
were >10000. Range is shown instead of SEM if one or more value is >10000. c µ selectivity calculated as δ IC50/µ IC50. NA indicates
insufficient binding potency at µ to obtain a selectivity value.
the tricyclic bridged series 32a -d and 34a ,b, based on
the single-crystal structure of the bis-fluoro analogues
32d , is shown in Scheme 4. Clearly, the substitution
patterns and electronic properties of the bis-phenyl rings
of these isopavines are important features in the relative
binding affinities to the three opioid receptors. These
functional features are better correlated with activity
in the series morphine, its monomethyl ether (codeine),
and its dimethyl ether (thebaine). The phenolic hydroxyl
group in morphine is a key functional feature for
binding to the µ receptor and for in vivo opioid activity.
Indeed, the binding of 3-deoxymorphine was 30-fold less
than the binding of morphine,71 and the monomethyl
ether codeine had a 200-fold lower affinity.72 On the
other hand, it has been recently shown that the intro-
duction of other pharmacophores in morphine as in the
14â-cinnamoylamino derivative of morphinone (clocin-
namox) can compensate for the absence of a phenolic
group.23 Table 2 lists the binding affinities of isopavine
analogues derived from L-amino acids (see Figure 1).51
Not surprisingly, 40a , which is enantiomeric with 7a ,
showed 3-fold weaker µ receptor binding but maintained
excellent selectivity (Table 2, entry 1). As the size of the
side chain was increased to isopropyl, isobutyl, and
benzyl, little effect was seen on µ affinity (which
diminished slightly) or κ affinity (which increased
slightly) (Table 2, entries 2-4). Introduction of polar
side chains seemed to have a similar effect with respect
to µ receptor binding but not with δ and κ (Table 2,
entries 5-7). The bis-methoxyphenyl analogue 40h ,
enantiomeric with O-methylthalisopavine 26a , showed
no binding to the three receptors (Table 2, entry 8).
Con clu sion
Diversely substituted dihydromethanodibenzoazo-
cines, which are readily available from D- and L-amino
acid precursors, undergo a stereocontrolled 1,2 Stevens
rearrangement to the corresponding isopavines. The
product originating from D-alanine and represented in
perspective drawings of isopavines A and A′ in Figure
1 are topologically related to morphine. A series of
substituted isopavines derived from D- and L-amino
acids with and without aromatic substituents were
synthesized and tested for their binding affinities
toward human opioid receptors.
Several analogues showed high affinity for the µ
opioid receptor, as well as good selectivity over δ and κ
receptors. The importance of the orientation of the
nitrogen lone pair to achieve morphine-like structural
features becomes evident when comparing isopavines
derived from D- and L-alanine. A mechanistic rationale
for the stereocontrolled 1,2 Stevens rearrangement is
presented. A functional assay on a representative µ
receptor selective analogue 13 showed agonist activity
at EC50 ) 4.3 µM and proved to be more efficacious than
morphine though less potent. Isopavines were shown
to be novel potential novel mimetics of morphine.
Exp er im en ta l Section
Solvents were distilled under positive pressure of dry
nitrogen before use and dried by standard methods: THF and
ether, from K/benzophenone; CH2Cl2 and toluene from CaCl2.
All commercially available reagents were used without further
purification. All reactions were performed under nitrogen
atmosphere. NMR (1H, 13C) spectra were recorded on AMX-
300 and ARX-400 spectrometers in CDCl3 or CD3OD with
tetramethylsilane as the internal standard. In some cases,
carbon resonances were coincident. Low- and high-resolution
mass spectra were recorded on VG Micromass, AEI-MS 902,
and Kratos MS-50 spectrometers using fast atom bombarde-
ment (FAB) or electrospray techniques. Optical rotations were
recorded on a Perkin-Elmer 241 polarimeter in a 1 dm cell at
ambient temperature. Analytical thin-layer chromatography
was performed on Merck 60F254 precoated silica gel plates.
Visualization was performed by UV or by development using
KMnO4 or FeCl3 solutions. Flash column chromatography was
Several isopavines showed µ opioid receptor binding
that was selective over δ by up to 80-fold (Table 1,
compounds 9, 10, 12, 13). Compound 13, which had
lower selectivity than these but retained excellent µ
affinity, showed agonist activity in stimulation of the
human µ receptor with an EC50 of 4.3 ( 1 µM. It showed
a higher maximal effect in stimulating the µ receptor
(100% vs 56% for morphine), but it was 10 times less
potent.

40 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 1
Hanessian et al.
performed using silica gel (40-60 µm) at increased pressure.
Na2SO4, and concentrated in vacuo. The crude product was
purified by flash chromatography using 10% MeOH/EtOAc as
the eluent system to give the desired azocine 6a (9.2 g, 78%)
as a white solid: mp 100-101 °C; [R]D -37.7° (c 1.0, CHCl3);
TLC Rf ) 0.50 (10% MeOH in EtOAc); 1H NMR (400 MHz,
CDCl3) δ 7.22 (m, 2H), 7.08 (m, 2H), 6.98 (m, 2H), 4.64 (d, 1H,
J ) 17.7 Hz), 4.54 (d, 1H, J ) 18.4 Hz), 4.02 (d, 1H, J ) 17.8
Hz), 3.89 (d, 1H, J ) 18.0 Hz), 3.64 (bs, 1H), 3.53 (dq, 1H, J )
1.6, 6.8 Hz), 1.22 (d, 3H, J ) 6.8 Hz); 13C NMR (100 MHz,
CDCl3) δ 141.6, 138.2, 133.7, 133.4, 128.3, 127.5, 126.2, 126.1,
126.0, 125.9, 125.8, 125.6, 59.7, 52.4, 52.1, 41.6, 17.5; HRMS
calcd for C17H18N 236.143 92 (M)+, found 236.142 90.
Melting points recorded were uncorrected.
N,N-Diben zyl-(R)-2-a m in o-1-p r op a n ol (5a ).56 D-Alanine
methyl ester (8.5 g, 60 mmol) and NaHCO3 (20.8 g, 240 mmol,
4.0 equiv) suspended in THF/DMSO (160 mL, 4:1) were treated
with benzyl bromide (14.3 mL, 120 mmol) at room tempera-
ture, and the solution was heated at reflux for 20 h. After
completion, the solid materials were removed by filtration, the
resulting filtrate was evaporated, and the residue was diluted
with EtOAc (80 mL). The organic phase was washed with
water and brine, dried over Na2SO4, concentrated in vacuo to
give the crude N,N-dibenzylated product as a viscous oil (16.5
g, 99%). The crude product was subjected to the next step
without purification. To a suspension of lithium aluminum
hydride (3.2 g, 84 mmol, 2.0 equiv) in dry THF (80 mL) was
added the above crude ester (16.2 g, 60 mmol, 1.0 equiv) in
THF (20 mL) at 0 °C, and the mixture was warmed to room
temperature. After 12 h of being stirred, the mixture was
cooled to 0 °C, excess hydride was quenched with EtOAc (3
mL), and then water (3 mL) and a 15% NaOH aqueous solution
(3 mL) were slowly added. Finally, water (9 mL) was added
and the mixture was filtered and washed with hot EtOAc. The
filtrates were concentrated in vacuo. The crude product was
purified by flash chromatography (hexane/EtOAc 1:1, then
neat EtOAc) to give the desired alcohol 5a (12.8 g, 84%) as a
viscous oil.
(13R)-13-Meth yl-(2,10-bism eth oxy)-7,12-d ih yd r o-5H-6,-
12-m eth a n od iben zo[c,f]a zocin e (6b). By use of the above
procedure, 5b (12.6 g) was subjected to Swern oxidation and
Friedel-Crafts cyclization to afford 6b (4.1 g, 35%) as a white
solid: mp 146-147 °C; [R]D -34.1° (c 1.0, CHCl3); TLC Rf )
0.32 (20% MeOH in EtOAc); 1H NMR (400 MHz, CDCl3) δ 6.89
(t, 2H, J ) 6.8 Hz), 6.71 (d, 2H, J ) 8.0 Hz), 6.59 (d, 2H, J )
7.5 Hz), 4.51 (d, 1H, J ) 18.0 Hz), 4.46 (d, 1H, J ) 18.3 Hz),
3.94 (d, 1H, J ) 17.9 Hz), 3.71 (d, 1H, J ) 18.0 Hz), 3.69 (s,
3H), 3.68 (s, 3H), 3.48 (s, 1H), 3.46 (m, 1H), 1.12 (d, 3H, J )
6.2 Hz); 13C NMR (100 MHz, CDCl3) δ 158.4, 158.3, 142.7,
139.4, 127.4, 127.1, 125.6, 125.3, 113.9, 113.2, 112.4, 112.2,
59.5, 55.7, 55.6, 52.6, 52.2, 42.7, 17.8; HRMS calcd for C19H21
-
NO2 295.380 42 (M)+, found 295.315 77.
(2R)-2-[Bis(4-m eth oxyben zyl)]a m in op r op a n e-1-ol (5b).
From D-alanine methyl ester (8.5 g, 61.0 mmol), 5b was
obtained in two steps (14.8 g, 83%) as a colorless, viscous oil:
[R]D -46.6° (c 1, CHCl3); TLC Rf ) 0.32 (40% EtOAc in
hexanes); 1H NMR (400 MHz, CDCl3) δ 7.25 (d, 4H, J ) 8 Hz),
7.16 (d, 4H, J ) 7.9 Hz), 3.78 (m, 2H), 3.75 (s, 6H), 3.73 (d,
2H, J ) 13 Hz), 3.25 (d, 2H, J ) 13.5 Hz), 2.94 (q, 1H, J ) 5.8
Hz), 1.76 (bs, 1H, -OH), 0.94 (d, 3H, J ) 6 Hz); 13C NMR (100
MHz, CDCl3) δ 159.2 (2C), 131.7 (2C), 130.5 (4C), 114.3 (4C),
(13R)-13-Meth yl-(2,10-bisbr om o)-7,12-d ih yd r o-5H-6,12-
m eth a n od iben zo[c,f]a zocin e (6c). By use of the above
procedure, 5c (18.1 g) was subjected to Swern oxidation and
Friedel-Crafts cyclization to afford 6c (12.97 g, 74%) as a
white solid: mp 196-197 °C; [R]D -82.3° (c 1.0, CHCl3); TLC
Rf ) 0.32 (5% MeOH in EtOAc); 1H NMR (400 MHz, CDCl3) δ
7.35 (s, 1H), 7.32 (s, 1H), 7.24 (dd, 2H, J ) 6.0, 8.0 Hz), 7.21
(dd, 2H, J ) 5.7, 8.0 Hz), 4.53 (d, 1H, J ) 18 Hz), 4.39 (d, 1H,
J ) 18.5 Hz), 3.94 (d, 1H, J ) 17.6 Hz), 3.76 (d, 1H, J ) 18.3
Hz), 3.48 (s, 1H), 3.43 (dq, 1H, J ) 6.8, 2 Hz), 1.16 (d, 3H, J
) 6.5 Hz); 13C NMR (100 MHz, CDCl3) δ 142.9, 139.7, 132.6,
132.3, 130.9, 130.2, 129.3, 129.2, 127.8, 127.4, 119.6, 119.5,
59.1, 51.9, 51.5, 41.0, 17.3; HRMS calcd for C17H15Br2N
392.120 33 (M - H)+, found 392.195 61.
(5S,6R,12R)-N-Meth yl-6-m eth ylisop a vin e (7a ). To a so-
lution of 6a (0.95 g, 4.0 mmol, 1.0 equiv) in dry acetone (5 mL)
was added iodomethane (0.75 mL, 12.0 mmol, 3.0 equiv) at
room temperature. The mixture was refluxed with stirring for
1 h. Evaporation of solvent and an excess of iodomethane gave
the desired quaternary salt, which was diluted with dry 1,4-
dioxane (10 mL), and potassium tert-butoxide (700 mg, 6.0
mmol, 1.5 equiv) was added. The mixture was warmed to 80
°C for 3 h. After the mixture was diluted with water, the
aqueous layer was extracted with dichloromethane. The
combined organic layers were washed with brine, dried over
Na2SO4, and concentrated in vacuo. The crude product was
purified by flash chromatography using 5-10% MeOH/EtOAc
as an eluent to give 7a (0.84 g, 85%) as a white solid: mp 82-
83 °C; TLC Rf ) 0.5 (5% MeOH in EtOAc); [R]D +149.8° (c 1,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.25-7.08 (m, 8H), 4.10
(t, 1H, J ) 3.3 Hz), 3.80 (dd, 1H, J ) 3.5, 17.8 Hz), 3.58 (s,
1H), 3.21 (q, 1H, J ) 6.5 Hz), 2.94 (dd, 1H, J ) 3.0, 18.0 Hz),
2.68 (s, 3H), 1.15 (d, 3H, J ) 6.3 Hz); 13C NMR (100 MHz,
CDCl3) δ 143.7, 140.6, 138.9, 134.6, 131.5, 127.5, 127.3, 126.4,
126.3, 126.2, 125.6, 124.8, 62.7, 61.5, 54.2, 40.3, 31.7, 22.8;
HRMS calcd for C18H19N 249.151 75 (M+), found 249.150 62.
65.4, 62.9, 55.7, 55.6, 54.2, 52.4, 9.0; HRMS calcd for C19H25
-
NO3 315.411 43 (M)+, found 315.418 12.
(2R)-2-[Bis(4-b r om ob en zyl)]a m in op r op a n e-1-ol (5c).
From D-alanine methyl ester (10 g, 71.0 mmol), 5c was
obtained in two steps (22.5 g, 79%) as a colorless, viscous oil:
[R]D -20.6° (c 3, CHCl3); TLC Rf ) 0.36 (40% EtOAc in
1
hexanes); H NMR (400 MHz, CDCl3) δ 7.39 (d, 2H, J ) 8.0
Hz), 7.18 (m, 4H), 7.09 (d, 2H, J ) 7.8 Hz), 3.83 (m, 1H), 3.77
(d, 2H, J ) 16.8 Hz), 3.42 (t, 1H, J ) 10.3 Hz), 3.29 (d, 2H, J
) 17.0 Hz), 2.89 (m, 1H), 0.95 (d, 3H, J ) 8.0 Hz); 13C NMR
(100 MHz, CDCl3) δ 138.5 (2C), 131.0 (4C), 131.1 (4C), 127.8
(2C), 63.2, 54.9, 54.7, 52.8, 9.1; LRMS (FAB, NBA, m/z, %)
412 (50) (M - H+), 382 (45), 207 (35), 169 (100), 147 (80).
Sw er n Oxid a tion of (5a ). To a solution of oxalyl chloride
(9.0 mL, 100 mmol, 2.0 equiv) in dry dichloromethane (80 mL)
was added DMSO (14.7 mL, 200 mmol, 4.0 equiv) at -78 °C.
After 5 min of strirring, the R-N,N-dibenzylamino alcohol 5a
(50 mmol, 12.5 g) diluted in dry dichloromethane (30 mL) was
added dropwise. The mixture was stirred for 30 min at -78
°C, and then triethylamine (57 mL, 400 mmol, 8.0 equiv) was
added and the mixture was warmed to room temperature for
30 min. Water (30 mL) was added, the layers were separated,
and the aqueous phase was extracted with dichloromethane.
The combined organic layers were sequentially washed with
1% HCl solution, water, saturated NaHCO3 solution, and brine
and dried over Na2SO4. Evaporation of solvent give the desired
R-N,N-dibenzylamino aldehyde, which was used immediately
in the next reaction.
(5S,6R,12R)-N-Meth yl(3,8-bism eth oxy)-6-m eth ylisop a -
vin e (7b). By use of the same procedure, 6b (1.24 g) was
subjected to Stevens rearrangement to give 7b (820 mg, 70%)
as a white solid: mp 72-73 °C; [R]D +136° (c 1.0, CHCl3); TLC
Rf ) 0.4 (20% MeOH in EtOAc); 1H NMR (400 MHz, CDCl3) δ
7.13 (d, 1H, J ) 8.0 Hz), 6.91 (d, 1H, J ) 7.8 Hz), 6.88-6.70
(m, 4H), 4.16 (t, 1H, J ) 3 Hz), 3.71 (s, 1H), 3.70 (s, 3H), 3.62
(dd, 1H, J ) 3.0, 17.5 Hz), 3.47 (s, 1H), 3.29 (q, 1H, J ) 6.3
Hz), 2.89 (dd, 1H, J ) 3.0, 18 Hz), 2.62 (s, 3H), 1.12 (d, 3H, J
) 6 Hz); 13C NMR (100 MHz, CDCl3) δ 159.1, 157.5, 143.5,
139.2, 132.0, 130.3, 126.5, 125.4, 112.9, 112.6, 112.1, 111.6,
(13R)-13-Meth yl-7,12-d ih yd r o-5H-6,12-m eth a n od iben -
zo[c,f]a zocin e (6a ). To a suspension of AlCl3 (26.2 g, 200
mmol, 4.0 equiv) in dry dichloromethane (120 mL) at 0 °C was
added via cannula the crude aldehyde obtained from the
corresponding alcohol (40 mmol, 1.0 equiv) in dry dichlo-
romethane (40 mL). The mixture was stirred for 1 h at 0 °C.
The red reaction mixture was diluted with dichloromethane
(50 mL) and quenched with saturated aqueous NaHCO3. After
the pH became basic (pH 8), the layers were separated and
the aqueous phase was extracted with dichloromethane. The
combined organic layers were washed with brine, dried over

Isopavines
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 1 41
63.8, 61.3, 55.2, 53.8, 40.3, 30.7, 21.8; HRMS calcd for C20H23
NO2 309.467 51 (M+), found 309.417 37.
-
diluted with 10% NaHCO3, and the aqueous phase was
continuously extracted with dichloromethane (5 × 20 mL). The
combined organic layer was dried over Na2SO4, filtered, and
condensed in vacuo. The crude product was purified by flash
column chromatography (eluent: MeOH/CHCl3, 1:4) to give
the bis-phenol 9 (106 mg, 76%) as a white solid: mp 195-196
°C; [R]D +93.6° (c 1.0, MeOH); TLC Rf ) 0.30 (30% MeOH in
(5S,6R,12R)-N-Met h yl(3,8-b isb r om o)-6-m et h ylisop a -
vin e (7c). By use of the same procedure, 6c (790 mg) was
subjected to Stevens rearrangement to give 7c (570 mg, 72%)
as an amorphous solid: mp 138-140 °C; [R]D +111.7° (c 1.0,
1
CHCl3); TLC Rf ) 0.34 (10% MeOH in EtOAc); H NMR (400
1
CHCl3); H NMR (300 MHz, CD3OD) δ 7.12 (d, 1H, J ) 8.5
MHz, CDCl3) δ 7.37(m, 4H), 7.02 (d, 1H, J ) 7.5 Hz), 6.82 (d,
1H, J ) 8.0 Hz), 4.02 (t, 1H, J ) 3 Hz), 3.64 (dd, 1H, J ) 3.0,
17.6 Hz), 3.47 (s, 1H), 3.12 (q, 1H, J ) 6.4 Hz), 2.82 (dd, 1H,
Hz), 6.81 (d, 1H, J ) 7.9 Hz), 6.76-6.71 (m, 4H), 4.26 (bs, 1H),
3.60 (dd, 1H, J ) 3.0, 18 Hz), 3.49 (s, 1H), 3.42 (q, 1H, J ) 6.3
Hz), 3.24 (bs, 2H), 2.90 (dd, 1H, J ) 3.3, 18 Hz), 2.74 (s, 3H),
1.20 (d, 3H, J ) 6.2 Hz); 13C NMR (75 MHz, CD3OD) δ 158.2,
155.7, 143.5, 139.6, 132.2, 127.3, 126.8, 123.2, 114.3, 114.2,
114.0, 113.9, 65.7, 62.5, 52.6, 39.5, 30.6, 19.9; HRMS calcd for
J ) 3.3 Hz, 18.0 Hz), 2.60 (s, 3H), 1.09 (d, 3H, J ) 6.3 Hz); 13
C
NMR (100 MHz, CDCl3) δ 144.8, 140.3, 139.1, 133.6, 132.8,
130.2, 129.5, 129.4, 126.5, 120.7, 119.2, 62.1, 60.7, 53.2, 39.9,
31.2, 22.6; LRMS (FAB, NBA, m/z, %) 408 (M + H+) (60), 328
(30), 236 (35), 154 (20), 136 (25); HRMS calcd for C18H17Br2N
407.147 02 (M)+, found 407.198 40.
C
18H19NO2 281.353 62 (M)+, found 281.314 13.
(5S,6R,12R)-N-Cyclop r op ylm et h yl(3,8-b ish yd r oxy)-6-
m eth ylisop a vin e (10). By use of the same procedure, 8c (106
mg) was refluxed in 3 mL of aqueous HBr for 3 h to give 10
(52 mg, 61%) as a pale-yellow solid: mp 160-162 °C; [R]D
-20.6° (c 2.0, MeOH); TLC Rf ) 0.4 (30% MeOH in CHCl3);
1H NMR (300 MHz, CD3OD) δ 7.09 (d, 1H, J ) 8.0 Hz), 6.87
(d, 1H, J ) 7.5 Hz), 6.85-6.46 (m, 4H), 4.34 (bs, 1H), 3.40
(dd, 1H, J ) 3.0, 18 Hz), 3.29 (s, 1H), 3.24 (m, 1H), 2.70 (dd,
1H, J ) 3.0, 18 Hz), 2.68 (m, 2H), 1.10 (d, 3H, J ) 6.5 Hz),
0.89 (m, 1H), 0.54 (m, 2H), 0.21 (m, 2H); 13C NMR (75 MHz,
CD3OD) δ 157.3, 155.4, 143.9, 140.6, 132.1, 126.8, 124.5, 114.2,
113.9, 113.8, 113.3, 63.5, 59.2, 58.9, 53.9, 31.7, 22.2, 8.9, 3.9,
(5S ,6R ,12R )-N -C y c lo p r o p y lm e t h y l-6-m e t h y lis o p a -
vin e (8a ). To a solution of 6a (200 mg, 0.85 mmol, 1.0 equiv)
and n-BuN4I (36 mg, 0.1 mmol) in dry acetone (2 mL) was
added cyclopropylmethyl bromide (0.30 mL, 3.0 mmol, 4.0
equiv) at room temperature. The mixture was refluxed with
stirring for 1 h. Evaporation of solvent and an excess of the
bromide gave the desired quaternary salt, which was diluted
with dry 1,4-dioxane (10 mL), and potassium tert-butoxide (230
mg, 2.0 mmol, 2.5 equiv) was added. The mixture was warmed
to 80 °C for 6 h. After the mixture was diluted with water,
the aqueous layer was extracted with dichloromethane. The
combined organic layers were washed with brine and dried
over Na2SO4 and concentrated in vacuo. The crude product
was purified by flash chromatography using 50-80% EtOAc/
hexane as the eluent to give the desired isopavine 8a (219 mg,
89%) as a viscous oil: [R]D +154.7° (c 1.0, CHCl3); TLC Rf )
0.7 (50% EtOAc in hexanes); 1H NMR (400 MHz, CDCl3) δ
7.12-7.38 (m, 10H), 4.51 (t, 1H, J ) 3.6 Hz), 3.75 (dd, 1H, J
) 3.3, 18.0 Hz), 3.61 (s, 1H), 3.32 (q, 1H, J ) 6.5 Hz), 2.96
(dd, 1H, J ) 3.0, 18.0 Hz), 2.82 (dd, 1H, J ) 6.0, 14.0 Hz),
2.62 (dd, 1H, J ) 6.3, 13.8 Hz), 1.18 (d, 3H, J ) 6.0 Hz), 1.08
(m, 1H), 0.63 (m, 1H), 0.59 (m, 1H), 0.32 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 143.3, 140.3, 139.4, 135.0, 131.1, 127.7,
127.1, 126.6, 126.4, 126.3, 125.7, 125.0, 61.9, 58.5, 58.1, 54.4,
32.8, 24.1, 10.7, 4.5, 3.7; HRMS calcd for C21H23N 289.419 40
(M)+, found 289.418 43.
(5S,6R,12R)-N-Cyclop r op ylm eth yl(3,8-bism eth oxy)-6-
m eth ylisop a vin e (8b). By use of the same procedure, 6b (320
mg) was subjected to Stevens rearrangement to give 8b (256
mg, 84%) as a yellow oil: [R]D +54.7° (c 1.0, CHCl3); TLC Rf )
0.5 (20% MeOH in EtOAc); 1H NMR (400 MHz, CDCl3) δ 7.09
(d, 1H, J ) 8.0 Hz), 6.88 (d, 1H, J ) 8.0 Hz), 6.64 (m, 4H),
4.43 (t, 1H, J ) 3.3 Hz), 3.75 (s, 3H), 3.74 (s, 3H), 3.52 (dd,
1H, J ) 3.0, 18.0 Hz), 3.47 (s, 1H), 3.32 (q, 1H, J ) 6.5 Hz),
2.79 (dd, 1H, J ) 3.3, 17.8 Hz), 2.69 (dd, 1H, J ) 3.3, 18.0
Hz), 2.53 (dd, 1H, J ) 6.0, 13.5 Hz), 1.13 (d, 3H, J ) 6 Hz),
0.96 (m, 1H), 0.53 (m, 2H), 0.17 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 158.7, 157.3, 143.9, 140.1, 132.0, 126.6, 125.9, 114.2,
112.9, 112.6, 111.8, 111.3, 61.6, 58.3, 57.8, 55.1, 54.7, 32.2, 23.9,
10.5, 4.2, 4.0, 3.6; HRMS calcd for C23H27NO2 349.600 83 (M)+,
found 349.602 30.
3.6; HRMS calcd for
321.417 34.
C
21H23NO2 321.418 20 (M+), found
(5S,6R,12R)-N-Meth yl(3,8-bisa cetoxy)-6-m eth ylisop a -
vin e (11). To a mixture of 9 (28 mg, 0.1 mmol) and DMAP (2
mg) in CH2Cl2 (5 mL) was added Et3N (0.070 mL, 0.5 mmol)
and pyridine (1 mL). The reaction mixture was cooled to 0 °C
and treated with acetic anhydride (0.050 mL, 0.5 mmol). The
resulting solution was warmed to room temperature for 12 h.
After completion, the reaction mixture was diluted with
dichloromethane (20 mL), washed with water, and brine. The
organic layer was dried over Na2SO4, filtered, and concentrated
in vacuo. The crude diacetate was purified by flash column
chromatography using MeOH/EtOAc (1:4) as the eluent to give
the pure diacetate 11 (31.7 mg, 89%) as a colorless oil: [R]D
+114.8° (c 1.0, CHCl3); TLC Rf ) 0.70 (30% MeOH in EtOAc);
1H NMR (300 MHz, CDCl3) δ 7.13 (d, 1H, J ) 8.0 Hz), 6.98 (d,
1H, J ) 7.8 Hz), 6.93-6.76 (m, 4H), 4.07 (t, 1H, J ) 3 Hz),
3.66 (dd, 1H, J ) 3.0, 18 Hz), 3.42 (s, 1H), 3.14 (q, 1H, J ) 6.3
Hz), 2.85 (dd, 1H, J ) 3.3, 17.8 Hz), 2.58 (s, 3H), 2.23 (s, 3H),
2.21 (s, 3H), 1.06 (d, 3H, J ) 6.0 Hz); 13C NMR (75 MHz,
CDCl3) δ 170.1, 169.8, 150.2, 148.7, 144.7, 140.1, 138.2, 132.7,
132.6, 126.2, 120.7, 120.2, 120.0, 119.9, 62.6, 61.3, 54.1, 40.4,
31.7, 23.0, 21.6, 21.5; HRMS calcd for C22H23NO4 365.428 04
(M)+, found 365.416 14.
(5S,6R,12R)-N-Cyclop r op ylm et h yl(3,8-b isa cet oxy)-6-
m eth ylisop a vin e (12). By use of the above procedure, 10 (20
mg) was subjected to acetylation to give 12 (23 mg, 79%) as a
viscous oil: [R]D +85.2° (c 2.0, CHCl3); TLC Rf ) 0.8 (20%
MeOH in EtOAc); 1H NMR (300 MHz, CD3OD) δ 7.18 (d, 1H,
J ) 8.0 Hz), 6.89 (d, 1H, J ) 7.5 Hz), 6.86-6.75 (m, 4H), 4.38
(bs, 1H), 3.57 (dd, 1H, J ) 3.2, 18 Hz), 3.43 (s, 1H), 3.20 (q,
1H, J ) 6.3 Hz), 2.83 (dd, 1H, J ) 3.3, 18.2 Hz), 2.64 (dd, 1H,
J ) 6.3, 14.5 Hz), 2.58 (dd, 1H, J ) 6.0, 13.2 Hz), 2.24 (s, 3H),
2.21 (s, 3H), 1.08 (d, 3H, J ) 6.5 Hz), 0.89 (m, 1H), 0.53 (m,
2H), 0.13 (m, 2H); 13C NMR (75 MHz, CD3OD) δ 170.0, 169.8,
150.2, 148.7, 144.2, 140.6, 132.9, 132.6, 126.5, 120.9, 120.2,
120.1, 119.9, 61.9, 58.4, 58.1, 54.4, 32.6, 30.1, 24.3, 21.5, 10.9,
4.9, 4.0; HRMS calcd for C25H27NO4 405.492 63 (M)+, found
405.491 43.
(5S,6R,12R)-N-Cyclop r op ylm eth yl(3,8-bisbr om o)-6-m e-
th ylisop a vin e (8c). By use of the same procedure, 6c (600
mg) was subjected to Stevens rearrangement to give 8c (540
mg, 81%) as a yellow oil: [R]D +110.4° (c 1.0, CHCl3); TLC Rf
1
) 0.9 (10% MeOH in EtOAc); H NMR (400 MHz, CDCl3) δ
7.38-6.89 (m, 6H), 4.42 (t, 1H, J ) 3.3 Hz), 3.55 (dd, 1H, J )
3.3, 18.0 Hz), 3.48 (s, 1H), 3.24 (q, 1H, J ) 6. Hz), 2.80 (dd,
1H, J ) 3.3, 17.8 Hz), 2.71 (m, 1H), 2.62 (m, 1H), 1.13 (d, 3H,
J ) 6.4 Hz), 0.89 (m, 1H), 0.62 (m, 1H), 0.56 (m, 1H), 0.20 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 144.3, 140.7, 132.8, 130.4,
129.7, 129.5, 129.4, 129.3, 127.7, 126.5, 120.6, 119.2, 61.5, 57.8,
(5S,6R,12R)-N-Met h yl(3,8-b isb en zyla m in o)-6-m et h yl-
isop a vin e (13). Into a flame-dried flask were placed sodium
tert-butoxide (15 mg, 0.15 mmol), tris(dibenzylidene acetone)-
dipalladium (3 mg, 0.0025 mmol, 5 mol %), and BINAP (4.6
mg, 0.0075 mmol) in toluene (2 mL). To the above pink solution
was added isopavine bis-bromide 7b (41 mg, 0.1 mmol) in
toluene (2 mL) followed by benzylamine (0.032 mL, 0.3 mmol),
which was introduced dropwise. The resulting solution was
53.5, 32.2, 23.8, 10.4, 4.4 (2C), 3.5; HRMS calcd for C21H21
-
Br2N 448.211 63 (M + H+), found 448.201 08.
(5S,6R,12R)-N-Meth yl(3,8-bish yd r oxy)-6-m eth ylisop a -
vin e (9). A solution of 7b (165 mg, 0.5 mmol) in 48% aqueous
HBr (3 mL) was heated to reflux at 120 °C for 3-4 h. The
resulting dark-brown solution was evaporated to dryness and

42 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 1
Hanessian et al.
stirred at 80 °C for 24-36 h. The reaction mixture was diluted
with water and extracted with dicholoromethane, and the
combined organic layers were washed with water and brine.
The organic phase was dried over Na2SO4, filtered, and
concentrated in vacuo. The crude bis-amine was purified by
flash column chromatography (MeOH/EtOAc, 1:4) to give
isopavine 13 (40 mg, 87%) as yellow viscous oil: [R]D -10.4°
(c 4.0, CHCl3); TLC Rf ) 0.30 (10% MeOH in EtOAC); 1H NMR
(300 MHz, CDCl3) δ 7.33-7.04 (m, 9H), 6.98 (d, 2H, J ) 8.0
Hz), 6.80 (d, 2H, J ) 7.8 Hz), 6.39 (m, 3H), 4.24 (d, 4H, J )
4.5 Hz), 3.98 (bs, 1H), 3.81 (bs, 2H, -NH), 3.62 (dd, 1H, J )
3.3, 18.2 Hz), 3.27 (s, 1H), 3.06 (q, 1H, J ) 6.0 Hz), 2.72 (dd,
1H, J ) 3.0, 17.8 Hz), 2.60 (s, 3H), 1.09 (d, 3H, J ) 6.0 Hz);
13C NMR (75 MHz, CDCl3) δ 148.1, 146.6, 139.9, 139.8, 132.5,
129.1 (3C), 129.0 (3C), 128.1 (3C), 128.0 (3C), 127.7, 127.6,
126.4, 112.2, 111.7, 110.9, 63.8, 61.6, 54.9, 48.9 (2C), 40.9, 31.9,
22.8; LRMS (FAB, NBA, m/z, %) 460.3 (60) (M + H+), 355 (25),
263 950), 154 (100), 137 (80); HRMS calcd for C32H33N3
459.632 81 (M)+, found 459.632 21.
58.5, 55.5, 49.0 (2C), 32.8, 24.6, 11.1, 4.7, 4.2; LRMS (FAB,
NBA, m/z, %) 500 (100) (M + H+), 339 (20), 303 (85), 201 (50),
154 (80); HRMS calcd for C35H37N3 500.697 45 (M + H+), found
500.697 40.
(5S,6R,12R)-N-Cyclop r op ylm et h yl(3,8-b isa n ilin o)-6-
m eth ylisop a vin e (18). By use of the above procedure, 7b (41
mg) was subjected to amination to give 18 (20 mg, 48%) as a
viscous oil: [R]D -34.7° (c 1.0, CHCl3); TLC Rf ) 0.30 (10%
MeOH in EtOAc); 1H NMR (300 MHz, CDCl3) δ 7.12-6.68 (m,
16H), 4.30 (bs, 1H), 3.60 (dd, 1H, J ) 3.3, 18.0 Hz), 3.28 (s,
1H), 3.18 (q, 1H, J ) 6.0 Hz), 2.86 (dd, 1H, J ) 3.0, 18.0 Hz),
2.68 (m, 1H), 2.54 (m, 1H), 1.96 (bs, 2H, -NH), 1.12 (d, 3H, J
) 6.5 Hz), 0.86 (m, 1H), 0.56 (m, 2H), 0.17 (m, 2H); 13C NMR
(75 MHz, CDCl3) δ 144.6, 143.0, 141.3, 133.3 (2C), 131.6, 130.9,
130.8, 130.3, 129.9 (2C), 129.8, 129.6, 128.8, 128.2, 127.7,
127.6, 127.4, 127.3, 127.0, 126.4, 125.6, 121.2, 119.7, 61.8, 58.6,
54.0, 32.8, 30.1, 24.4, 10.9, 4.9, 4.0; LRMS (FAB, NBA, m/z,
%) 472 (25) (M + H+), 381 (75), 289 (35), 147 (40); HRMS calcd
for C33H33N2 471.990 12 (M)+, found 471.989 41.
(5S,6R,12R)-N-Met h yl(3,8-b isa n ilin o)-6-m et h ylisop a -
vin e (14). By use of the above procedure, 7b (43 mg) was
subjected to amination to give 14 (30 mg, 66%) as a pink
solid: mp 79-80 °C; [R]D -36.0° (c 1.0, CHCl3); TLC Rf ) 0.34
(5S,6R,12R)-N-Cyclopr opylm eth yl(3,8-bis-N-m eth ylpip-
er a zin ea m in o)-6-m eth ylisop a vin e (19). By use of the above
procedure, 7b (41 mg) was subjected to amination to give 19
(30 mg, 61%) as a yellow viscous oil: [R]D +7.2° (c 1.0, CHCl3);
TLC Rf ) 0.58 (10% MeOH in CHCl3); 1H NMR (300 MHz,
CDCl3) δ 7.29-6.68 (m, 6H), 4.41 (bs, 1H), 3.52 (dd, 1H, J )
3.0, 18.0 Hz), 3.49 (s, 1H), 3.23 (q, 1H, J ) 6.5 Hz), 3.12 (bs,-
8H), 2.71 (dd, 1H, J ) 3.0, 18.0 Hz), 2.68 (m, 2H), 2.49 (bs,
8H), 2.36 (s, 6H), 1.14 (d, 3H, J ) 6.0 Hz), 0.99 (m, 1H), 0.59
(m, 2H), 0.17 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 149.1,
143.5, 138.9, 131.7, 128.3, 127.1, 126.8, 126.5, 126.4, 125.0,
115.3, 114.2, 61.9, 58.7, 58.1, 54.9 (4C), 54.6 (2C), 49.0 (2C),
45.8 (2C), 31.7, 23.7, 10.3, 3.7 (2C), 3.5; LRMS (FAB, NBA,
m/z, %) 466 (15) (M - NH3+), 388 (100), 290 (25), 198 (50),
154 (50); HRMS calcd for C31H43N5 485.714 23 (M)+, found
485.714 12.
(5S,6R,12R)-6-Meth ylisop a vin e (20). To a solution of 7a
(410 mg, 1.6 mmol) in MeOH (10 mL) was added Pd/C (1.0 g,
10%) at 0 °C, and the reaction mixture was stirred at room
temperature in open-air atmosphere for 24 h.63 The mixture
was filtered through Celite and washed with 30% MeOH in
EtOAc. The combined filtrates were dried over Na2SO4 and
concentrated in vacuo. The crude product was flash-chromato-
graphed on silica gel to give pure amine 20 (298 mg, 84%) as
a colorless oil: [R]D +99.3° (c 1.0, CHCl3); TLC Rf ) 0.32 (10%
MeOH in CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.20-7.01 (m,
8H), 4.28 (t, 1H, J ) 3.6 Hz), 3.91 (q, 1H, J ) 6.5 Hz), 3.49
(dd, 1H, J ) 3.0, 18.0 Hz), 3.46 (bs, 1H, -NH), 3.33 (s, 1H),
3.20 (dd, 1H, J ) 3.7 Hz, 18.0 Hz), 1.05 (d, 3H, J ) 6.5 Hz);
13C NMR (75 MHz, CDCl3) δ 143.5, 140.0, 139.8, 135.3, 131.7,
128.2, 127.8, 127.5, 127.3, 127.1, 126.3, 125.1, 56.2, 55.3, 53.3,
40.0, 24.2; LRMS (FAB, NBA, m/z, %) 236 (100) (M)+, 219 (25),
192 (30), 91 (10); HRMS calcd for C17H17N 236.328 02 (M)+,
found 236.319 60.
(5S,6R,12R)-N-Allyl-6-m eth ylisop a vin e (21). A mixture
of 20 (25 mg, 0.1 mmol), Na2CO3 (106 mg, 1 mmol), and
n-BuN4I (36 mg, 0.01 mmol) in EtOH (3 mL) was treated with
allyl bromide (0.045 mL, 0.5 mmol), and the resulting solution
was heated to reflux for 12 h. The solvent was evaporated,
and the crude product was diluted with ether (20 mL) and
washed with water and brine. The organic phase was dried
over Na2SO4, filtered, and concentrated in vacuo. The pure
product was obtained by flash chromatography to give N-
allylisopavine 21 (27 mg, 98%) as a highly viscous oil: [R]D
+148.8° (c 2.6, CHCl3); TLC Rf ) 0.70 (50% EtOAc in hexanes);
1H NMR (300 MHz, CDCl3) δ 7.23-7.02 (m, 8H), 5.97 (m, 1H),
5.12 (dd, 2H, J ) 9.0, 34 Hz), 4.16 (t, 1H, J ) 3.3 Hz), 3.67
(dd, 1H, J ) 3.0, 18.0 Hz), 3.53 (s, 1H), 3.44 (d, 2H, J ) 6.5
Hz), 3.26 (q, 1H, J ) 6.0 Hz), 2.86 (dd, 1H, J ) 3.0, 18.0 Hz),
1.04 (d. 3H, J ) 6.0 Hz); 13C NMR (75 MHz, CDCl3) δ 143.7,
140.7, 139.8, 135.4, 131.6, 128.2, 127.7, 127.1, 127.0, 126.8,
126.3, 125.4, 117.6, 62.2, 58.2, 56.8, 54.7, 33.0, 24.0; LRMS
(FAB, NBA, m/z, %) 276.2 (100) (M + H+), 260 (30), 236 (15),
219 (30), 192.2 (75), 91 (20); HRMS calcd for C20H21N 275.392 63
(M)+, found 275.316 78.
1
(10% MeOH in EtOAC); H NMR (300 MHz, CDCl3) δ 7.24-
6.78 (m, 16H), 3.97 (bs, 1H), 3.36 (dd, 1H, J ) 3.3, 18.0 Hz),
3.32 (s, 1H), 3.09 (q, 1H, J ) 6.5 Hz), 2.82 (dd, 1H, J ) 3.0,
18.0 Hz), 2.59 (s, 3H), 2.01 (bs, 2H, -NH), 1.08 (d, 3H, J ) 6
Hz); 13C NMR (75 MHz, CDCl3) δ 145.0, 143.9, 143.8, 142.4,
132.6, 129.8 (3C), 129.7 (3C), 127.9, 126.7, 126.3, 121.0, 120.9,
117.8 (2C), 117.7 (2C), 117.4, 117.1, 116.8, 116.5, 63.1, 61.6,
54.7, 39.9, 31.8, 23.2; LRMS (FAB, NBA, m/z, %) 432 (25) (M
+ H+), 341 (30), 325 (15), 249 (45), 219 (80), 147 (100); HRMS
calcd for C30H29N3 431.282 25 (M)+, found 431.282 02.
(5S ,6R ,12R )-N -Me t h yl(3,8-b is-N -m e t h ylp ip e r a zin e -
a m in o)-6-m eth ylisop a vin e (15). By use of the above proce-
dure, 7b (40 mg) was subjected to amination to give 15 (31
mg, 69%) as a yellow solid: mp 72-74 °C; [R]D -11.9° (c 1.4,
1
CHCl3); TLC Rf ) 0.23 (10% MeOH in CHCl3); H NMR (300
MHz, CDCl3) δ 6.65-7.08 (m, 6H), 4.01 (t, 1H, J ) 3.3 Hz),
3.66 (dd, 1H, J ) 3.3, 18.0 Hz), 3.43 (s, 1H), 3.13 (m, 9H), 2.89
(dd, 1H, J ) 3.0, 18.0 Hz), 2.59 (s, 6H), 2.54 (m, 8H), 2.31 (s,
3H), 1.09 (d, 3H, J ) 6.0 Hz); 13C NMR (75 MHz, CDCl3) δ
151.2, 144.0, 139.9, 135.3, 132.3, 131.6, 128.1, 126.8, 126.2,
126.1, 115.5, 114.3, 63.6, 61.3, 55.5 (4C), 54.9 (2C), 49.7 (2C),
46.4, 40.8, 32.7, 22.9; LRMS (FAB, NBA, m/z, %) 443 (40) (M
- H2+), 385 (15), 281 (25), 207 (50), 191 (40), 147 (100); HRMS
calcd for C30H29N3 445.6496 (M+), found 445.6491.
(5S,6R,12R)-N-Meth yl(3,8-bism or p h olin ea m in o)-6-m e-
th ylisop a vin e (16). By use of the above procedure, 7b (42
mg) was subjected to amination to afford 16 (46 mg, 99%) as
a yellow solid: mp 102-104 °C; [R]D +59.6° (c 4.0, CHCl3);
TLC Rf ) 0.53 (10% MeOH in EtOAc); 1H NMR (300 MHz,
CDCl3) δ 7.06-6.60 (m, 6H), 3.97 (bs, 1H), 3.79 (d, 8H, J )
4.5 Hz), 3.59 (dd, 1H, J ) 3.3, 18.0 Hz), 3.36 (s, 1H), 3.06 (d,
8H, J ) 4.9 Hz), 2.79 (dd, 1H, J ) 3.0, 18.0 Hz), 2.57 (s, 3H),
1.05 (d, 3H, J ) 6.0 Hz); 13C NMR (75 MHz, CDCl3) δ 151.2,
149.6, 144.8, 139.9, 132.4 (2C), 126.7, 126.0, 115.4, 115.2,
114.4, 114.0, 67.4 (4C), 63.3, 61.3, 55.5, 50.3 (2C), 50.1 (2C),
40.8, 31.7, 23.2; LRMS (FAB, NBA, m/z, %) 420 (50) (M + H+),
335 (35), 243 (65), 154 (90), 136 (100); HRMS calcd for
C
26H33N3O2 419.565 62 (M+), found 419.565 59.
(5S,6R,12R)-N-Cyclopr opylm eth yl(3,8-bisben zylam in o)-
6-m eth ylisop a vin e (17). By use of the above procedure, 7b
(41 mg) was subjected to amination to give 17 (33 mg, 66%)
as a viscous oil: [R]D +138° (c 1.0, CHCl3); TLC Rf ) 0.50 (10%
MeOH in EtOAc); 1H NMR (300 MHz, CDCl3) δ 7.70-6.96 (m,
11H), 6.75 (d, 2H, J ) 8.0 Hz), 6.36 (m, 3H), 4.24 (bs, 4H),
3.79 (bs, 1H), 3.46 (dd, 1H, J ) 3.0, 18.0 Hz), 3.21 (s, 1H),
3.14 (q, 1H, J ) 4.8 Hz), 2.53 (dd, 1H, J ) 3.0, 18.5 Hz), 2.51
(m, 1H), 2.49 (m, 1H), 1.84 (bs, 2H, -NH), 1.09 (d, 3H, J )
6.0 Hz), 0.86 (m, 1H), 0.51 (m, 2H), 0.15 (m, 2H); 13C NMR
(75 MHz, CDCl3) δ 147.8, 146.5, 140.0, 132.9, 132.8, 132.5,
132.4, 129.0 (2C), 128.9 (2C), 128.4, 128.2, 128.1 (2C), 128.0
(2C), 127.6 127.5, 126.2, 112.4, 112.1, 111.6, 110.8, 62.3, 59.0,

Isopavines
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 1 43
(5S,6R,12R)-N-Ben zyl-6-m eth ylisop a vin e (22). A mix-
ture of 20 (25 mg, 0.1 mmol), Na2CO3 (106 mg, 1.0 mmol), and
n-BuN4I (36 mg, 0.01 mmol) in EtOH (3 mL) was treated with
benzyl bromide (0.035 mL, 0.3 mmol), and the resulting
solution was refluxed for 12 h. The solvent was evaporated,
and the crude product was diluted with ether (20 mL) and
washed with water and brine. The organic phase was dried
over Na2SO4, filtered, and concentrated in vacuo. The pure
product was obtained by flash chromatography to give 22 (36.8
mg, 99%) as a white solid: mp 165-166 °C; [R]D +111° (c 1.0,
CHCl3); TLC Rf ) 0.80 (50% EtOAc in hexanes); 1H NMR (300
MHz, CDCl3) δ 7.42-7.03 (m, 13H), 3.97 (bs, 3H), 3.75 (dd,
1H, J ) 3.0, 18 Hz), 3.60 (s, 1H), 3.42 (q, 1H, 6.0 Hz), 2.83
(dd, 1H, J ) 2.9, 18.0 Hz), 1.08 (d, 3H, J ) 6.2 Hz); 13C NMR
(75 MHz, CDCl3) δ 143.8, 139.9, 135.6, 131.7, 129.2, 128.9,
128.8, 128.2, 128.1, 127.9, 127.5, 127.4, 127.2, 127.0, 126.8,
126.3, 125.1, 73.2, 62.5, 54.9, 32.9, 24.0, 15.7; LRMS (FAB,
NBA, m/z, %) 326 (100) (M + H+), 234 (30), 192 (25), 154 (45),
91 60); HRMS calcd for C24H23N 325.452 41 (M)+, found
325.418 23.
(5S,6R,12R)-N-Acetyl-6-m eth ylisop a vin e (23). To a mix-
ture of isopavine 20 (30 mg, 0.14 mmol) and DMAP (2 mg) in
CH2Cl2 (5 mL) was added Et3N (0.10 mL, 0.75 mmol) and
pyridine (0.5 mL). The reaction mixture was cooled to 0 °C
and treated with acetic anhydride (0.050 mL, 0.5 mmol). The
resulting solution was warmed to room temperature for 12 h.
After completion, the mixture was diluted with dichlo-
romethane (20 mL) and washed with water and brine. The
organic layer was dried over Na2SO4, filtered, and concentrated
in vacuo. The crude acetate was purified by flash column
chromatography using MeOH/EtOAc (1:4) as the eluent to give
the pure diacetate 23 (37.7 mg, 97%) as an amorphous solid:
mp 63-64 °C; [R]D +198.7° (c 8.0, CHCl3); TLC Rf ) 0.70 (10%
MeOH in EtOAc); 1H NMR (300 MHz, CDCl3) δ (major
rotamer) 7.27-6.97 (m, 8H), 6.01 (t, 1H, J ) 2.5 Hz), 4.06 (q,
1H, J ) 3.0 Hz), 4.02 (dd, 1H, J ) 3.0, 12.0 Hz), 3.51 (s, 1H),
2.83 (d, 1H, J ) 12 Hz), 1.81 (s, 3H), 0.78 (d, 3H, J ) 4.8 Hz,
67%); 1H NMR (300 MHz, CDCl3) δ (rotamer B, minor, amide)
7.29-6.99 (m, 8H), 5.13 (q, 1H, J ) 3.0 Hz), 4.66 (t, 1H, J )
2.8 Hz), 3.56 (s, 1H), 3.16 (dd, 1H, J ) 3.3, 18.0 Hz), 2.71 (d,
1H, J ) 12 Hz), 2.01 (s, 3H), 1.28 (d, 3H, J ) 4.6 Hz, 33%);
13C NMR (75 MHz, CDCl3) δ 170.5, 139.3, 137.1, 135.5, 132.1,
129.3, 128.2, 128.0, 127.9, 127.7, 126.9, 126.5, 126.2, 58.1, 56.3,
54.7, 39.8, 22.6, 22.1; LRMS (FAB, NBA, m/z, %) 278 (100) (M
+ H+), 234 910), 219 (20), 192 (20), 154 (30), 107 (10); HRMS
calcd for C19H19NO 277.365 23 (M+), found 277.314 73.
From 25 (525 mg), after Stevens rearrangement, 26a was
obtained as a white solid (417 mg, 76%): mp 122-123 °C; [R]D
+111.0° (c 1, CHCl3); TLC Rf ) 0.35 (20% MeOH in EtOAc);
1H NMR (400 MHz, CDCl3) δ 6.69 (d, 2H, J ) 4.8 Hz), 6.54 (s,
1H), 6.45 (s, 1H), 3.91 (s, 1H), 3.76 (s, 3H), 3.74 (s, 3H), 3.73
(s, 3H), 3.66 (s, 3H), 3.52 (dd, 1H, J ) 3.0, 18.0 Hz), 3.28 (s,
1H), 3.0 (q, 1H, J ) 6.0 Hz), 2.76 (dd, 1H, J ) 3.0, 18.0 Hz),
2.51 (s, 3H), 0.99 (d, 3H, J ) 6.0 Hz); 13C NMR (100 MHz,
CDCl3) δ 148.2, 147.8, 147.7, 146.8, 136.8, 132.8, 132.0, 126.7,
114.6, 111.4, 110.7, 109.7, 63.6, 61.6, 56.3 (3C), 56.2, 53.5, 40.6,
32.0, 23.2; HRMS calcd for C22H27NO4 370.459 63 (M + H+),
found 370.420 53.
(5S,6R,12R)-N-Cyclop r op ylm eth yl(3,8-bism eth oxy)-6-
m eth ylisop a vin e (26b). Typical procedure as described for
8b was followed. From 25 (360 mg), after Stevens rearrange-
ment, 26b was obtained as a viscous oil (345 mg, 87%): [R]D
+114° (c 1, CHCl3); TLC Rf ) 0.35 (10% MeOH in EtOAc); 1H
NMR (400 MHz, CDCl3) δ 6.76 (s, 1H), 6.73 (s, 1H), 6.56 (s,
1H), 6.45 (s, 1H), 4.26 (bs, 1H), 3.80 (s, 3H), 3.79 (s, 6H), 3.69
(s, 3H), 3.52 (dd, 1H, J ) 3.3, 18.0 Hz), 3.31 (s, 1H), 3.15 (q,
1H, J ) 6.0 Hz), 2.75 (dd, 1H, J ) 3.0, 18.0 Hz), 2.64 (dd, 1H,
J ) 6.0, 14.0 Hz), 2.54 (dd, 1H, J ) 6.0, 14.0), 1.04 (d, 3H, J
) 6.0 Hz), 0.91 (m, 1H), 0.49 (t, 2H, J ) 10.0 Hz), 0.14 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 148.2, 147.8, 147.7, 146.9,
136.4, 132.7, 132.4, 126.9, 114.5, 111.5, 110.8, 109.9, 62.8, 58.9,
58.7, 56.5, 56.4, 56.3, 56.2, 53.8, 32.9, 24.5, 11.2, 4.8, 4.1; LRMS
(FAB, NBA, m/z, %) 410 (100) (M + H+), 339 (45), 258 (80),
154 (90); HRMS calcd for C25H31NO4 409.524 21 (M)+, found
409.512 87.
Typ ica l P r oced u r e for N-N-Diben zyl-(S)-2-a m in o-1,5-
p en ta n ed iol (27a ). A mixture of L-glutamic acid diester (10
g, 41.8 mmol) and NaHCO3 (13.8 g, 167 mmol, 4.0 equiv)
suspended in THF/DMSO (100 mL, 4:1) was treated with
benzylbromide (9.98 mL, 84 mmol) at room temperature and
allowed to reflux for 20 h. After completion, the solid materials
were removed by filtration and the resulting filtrate was
concentrated and then diluted with EtOAc (80 mL). The
organic phase was washed with water and brine, dried over
Na2SO4, and evaporated in vacuo to give the crude N,N-
dibenzylated product as a viscous oil (16.1 g, 99%), which was
used in the next step without purification.
To a suspension of lithium aluminum hydride (3.2 g, 84
mmol, 2.0 equiv) in dry THF (80 mL) was added the above
crude diester (16.2 g, 41 mmol, 1 equiv) in THF (20 mL) at 0
°C, and the mixture was warmed to room temperature. After
12 h of being stirred, the mixture was cooled to 0 °C. Excess
hydride was quenched with EtOAc (3 mL) and then water (3
mL), and a 15% NaOH aqueous solution (3 mL) was slowly
added. Finally, water (9 mL) was added and the mixture was
filtered and washed with hot EtOAc. The filtrates were
concentrated in vacuo. The crude product was purified by flash
chromatography (hexane/EtOAc 1:1, then neat EtOAc) to give
the desired diol 27a (11.2 g, 90%) as a viscous oil: 1H NMR
(400 MHz, CDCl3) δ 7.39-7.22 (m, 10H), 3.83 (d, 2H, J ) 18.0
Hz), 3.65 (t, 2H, J ) 6.5 Hz), 3.51-3.49 (m, 4H), 2.83 (m, 1H),
1.89 (m, 1H), 1.52 (m, 3H), 1.36 (m, 1H). The crude diol 27a
was used in the next step.
(2R)-2-[Bis-3,4-d im et h oxyben zyl)]a m in op r op a n e-1-ol
(24). By use of the reported procedure,56 D-alanine methyl ester
(from 5 g, 35.0 mmol) was subjected to dimethoxybenzylation
and LAH reduction to give 24 (10.8 g, 78%) as a clear viscous
oil: [R]D -29° (c 1, CHCl3); TLC Rf ) 0.36 (50% EtOAc in
hexanes); 1H NMR (400 MHz, CDCl3) δ 6.82-6.66 (m, 6H),
3.78 (s, 4H), 3.76 (s, 6H), 3.74 (s, 6H), 3.36 (m, 2H), 2.92 (m,
1H), 0.91 (d, 3H, J ) 6.0 Hz); 13C NMR (100 MHz, CDCl3) δ
149.3, 148.7, 148.5, 147.5, 134.2, 133.8, 132.2, 120.8, 119.6,
112.2, 111.3, 110.7, 65.3, 62.9, 56.2, 53.9, 52.9, 9.2; HRMS calcd
for C21H29NO5 376.463 83 (M + H+), found 376.421 35.
(13R)-13-Meth yl-(2,10-bism eth oxy)-7,12-d ih yd r o-5H-6,-
12-m eth a n od iben zo[c,f]a zocin e (25). The general procedure
as described for 6b was followed. A quantity of 24 (8.3 g) was
subjected to Swern oxidation and Friedel-Crafts cyclization
to give 25 as a yellow amorphous solid (3.9 g, 48%): mp 94-
95 °C; [R]D -15.5° (c 1, CHCl3); TLC Rf ) 0.30 (20% MeOH in
EtOAc); 1H NMR (400 MHz, CDCl3) δ 6.57 (d, 2H, J ) 10 Hz),
6.34 (d, 2H, J ) 3.5 Hz), 4.37 (d, 1H, J ) 18.0 Hz), 4.26 (d,
1H, J ) 18.0 Hz), 3.74 (d, 1H, J ) 17.5 Hz), 3.72 (s, 3H), 3.69
(s, 3H), 3.60 (d, 1H, J ) 18.0 Hz), 3.58 (s, 6H), 3.30 q, 1H, J )
6.5 Hz), 3.19 (s, 1H), 1.03 (d, 3H, J ) 6.5 Hz); 13C NMR (100
MHz, CDCl3) δ 147.8 (2C), 147.6, 134.4, 131.0, 125.8, 125.5,
111.6, 110.8, 109.3, 109.1, 59.9, 56.4 (4C), 56.1, 52.8, 52.6, 40.9,
17.6; HRMS calcd for C21H25NO4 356.432 81 (M + H+), found
356.418 87.
(2S)-2-[Bis-(4-m et h oxyb en zyl)a m in o]p en t a n e-1,5-d i-
ol (27b). By use of the above procedure, 15.5 g of L-glutamic
acid diester was subjected to 4-methoxybenzylation and LiAlH4
reduction to give 27b as a viscous oil: [R]D +44.2° (c 1, CHCl3);
1
TLC Rf ) 0.35 (50% EtOAc in hexanes); H NMR (400 MHz,
CDCl3) δ 7.17 (d, 4H, J ) 8.5 Hz), 6.85 (d, 4H, J ) 8.7 Hz),
3.78 (s, 3H), 3.74 (s, 3H), 3.68 (d, 2H, J ) 12.9 Hz), 3.62 (t,
2H, J ) 6.5 Hz), 3.45 (m, 2H), 3.37 (d, 2H, J ) 13.1 Hz), 2.80
(q, 1H, J ) 4.5 Hz), 1.80 (m, 1H), 1.50 (m, 2H), 1.30 (m, 1H);
13C NMR (100 MHz, CDCl3) δ 158.6 (4C), 130.0 (4C), 113.7
(4C), 62.5, 60.5, 58.3, 55.1 (2C), 52.2 (2C), 30.0, 21.2; LRMS
(FAB, NBA, m/z, %) 360 (20) (M + H+), 328 (25), 281 (15), 207
(45), 190 (45); HRMS calculated for C21H30NO4 (M + H+):
360.217 50, found 360.216 30.
(2S)-2-[Bis-(4-br om oben zyl)am in o]pen tan e-1,5-diol (27c).
By use of the same procedure, 2.3 g of L-glutamic acid diester
was subjected to 4-bromobenzylation and LiAlH4 reduction to
(5S,6R,12R)-N-Meth yl(3,8-bism eth oxy)-6-m eth ylisop a -
vin e (26a ). Typical procedure described for 7b was followed.

44 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 1
give 27c (1.34 g, 74%) as a viscous oil: [R]D +13.8° (c 1, CHCl3);
Hanessian et al.
1
1, CHCl3); TLC Rf ) 0.46 (20% EtOAc in hexanes); H NMR
1
TLC Rf ) 0.40 (50% EtOAc in hexanes); H NMR (400 MHz,
(400 MHz, CDCl3) δ 7.20 (m, 4H), 7.02 (m, 4H), 4.05 (t, 2H, J
) 6.3 Hz), 3.75 (d, 2H, J ) 13.3 Hz), 3.52 (m, 2H), 3.40 (d, 2H,
J ) 13.3 Hz), 2.79 (m, 1H), 1.78 (m, 1H), 1.60 (m, 2H), 1.30
(m, 1H), 1.22 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 178.3,
163.1, 160.7, 134.6 (2C), 130.3 (2C), 130.2 (2C), 115.3 (2C),
115.1 (2C), 63.8, 60.7, 58.5, 52.3 (2C), 38.6, 27.0 (3C), 26.2,
21.5; LRMS (EI, m/z, %) 418 (60) (M - H+), 388 (40), 109 (75);
HRMS calculated for C24H30NO3F2 (M - H+): 418.219 36,
found 418.220 00.
CDCl3) δ 7.48 (d, 4H, J ) 8.5 Hz), 7.08 (d, 4H, J ) 8.0 Hz),
3.69 (d, 2H, J ) 17.5 Hz), 3.58 (t, 2H, J ) 6.8 Hz), 3.51 (m,
2H), 3.47 (d, 2H, J ) 16.8 Hz), 2.71 (m, 1H), 1.79 (m, 1H),
1.52 (m, 2H), 1.39 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 138.0
(2C), 131.5 (4C), 130.4 (4C), 121.0 (2C), 62.3 (2C), 60.8, 58.8,
52.6 (2C), 29.9, 21.4; LRMS (FAB, NBA, m/z, %) 458 (80) (M
+ H+), 426 (100), 169 (95), 136 (25), 91 (15).
(2S)-2-[Bis(4-flu or oben zyl)am in o]pen tan e-1,5-diol (27d).
By use of the same procedure, 4.8 g of L-glutamic acid diester
was subjected to 4-fluorobenzylation and LiAlH4 reduction to
(13S)-2,2-Dim eth ylp r op ion ic Acid 3-(7,12-Dih yd r o-5H-
6,12-m eth a n od iben zo[c,f]a zocin -13-yl)p r op yl Ester (29a ).
To a solution of oxalyl chloride (5.2 mL, 60.0 mmol, 5 equiv)
in dry dichloromethane (30 mL) was added, at -78 °C, DMSO
(8.43 mL, 120 mmol, 10 equiv). After 5 min of stirring, the
R-N,N-dibenzylamino alcohol (4.78 g, 120.0 mmol, 1.0 equiv)
diluted in dry dichloromethane (30 mL) was added. The
mixture was stirred for 30 min at -78 °C, and then triethy-
lamine (24.2 mL,175.0 mmol, 15 equiv) was added and the
mixture was warmed to room temperature for 30 min. Water
(20 mL) was added, the layers were separated, and the
aqueous phase was extracted with dichloromethane. The
combined organic layers were successfully washed with 1%
HCl solution, water, saturated NaHCO3 solution, and brine
and dried over Na2SO4. Evaporation of solvent give the desired
R-N,N-dibenzylamino aldehyde, which was used immediately
in the next reaction.
To a suspension of AlCl3 (4.8 g, 36.0 mmol, 3.0 equiv) in
dry dichloromethane (60 mL) at 0 °C was added via cannula
the crude aldehyde obtained from the corresponding alcohol
(12 mmol, 1.0 equiv) in dry dichloromethane (40 mL). The
mixture was stirred for 12 h at room temperature. AlCl3 (2.4
g, 18.0 mmol, 1.5 equiv) was added to complete the reaction.
After 2 h of being stirred, the red reaction mixture was diluted
with dichloromethane and quenched with saturated aqueous
sodium hydrogen carbonate solution. After the pH became
basic (pH 8), the layers were separated and the aqueous phase
was extracted with dichloromethane. The combined organic
layers were washed with brine, dried over Na2SO4, and
concentrated in vacuo. The crude product was purified by
chromatography to give 29a (3.6 g, 85%) as a white solid: [R]D
+26.5° (c 1, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.25 (m,
2H), 7.12 (m, 4H), 7.00 (m, 2H), 4.62 (d, 1H, J ) 17.7 Hz),
4.47 (d, 1H, J ) 18.4 Hz), 4.05 (m, 3H), 3.85 (d, 1H, J ) 18.4
Hz), 3.65 (s, 1H), 3.35 (m, 1H), 1.90 (m, 1H), 1.82 (m, 1H),
1.61 (m, 1H), 1.50 (m, 1H), 1.18 (s, 9H); 13C NMR (100 MHz,
CDCl3) δ 178.3, 141.2, 138.1, 133.9, 133.6, 128.0, 127.5, 126.2,
126.1, 126.0, 125.9, 125.8, 125.5, 64.0, 59.9, 56.4, 52.3, 40.4,
38.5, 27.4, 27.0 (3C), 25.6; LRMS (EI, m/z, %): 364 (100) (M +
H+), 278 (30), 262 (15), 218 (20), 192 (40), 154 (20), 91 (60);
HRMS calculated for C24H30NO2 (M + H+): 364.227 66, found
364.226 40.
(13S)-2,2-Dim eth ylp r op ion ic Acid 3-(2,10-Dim eth oxy-
7,12-d ih yd r o-5H-6,12-m eth a n od iben zo[c,f]a zocin -13-yl)-
p r op yl Ester (29b). By use of the same procedure, 28b (4.8
g) was subjected to Swern oxidation and Friedel-Crafts
reaction to give 29b (1.36 g, 33%) as a viscous oil: [R]D +13.1°
(c 1, CHCl3); TLC Rf ) 0.20 (50% EtOAc in hexanes); 1H NMR
(400 MHz, CDCl3) δ 6.87 (2d, 2H, J ) 8.5 Hz), 6.83 (d, 2H, J
) 7.8 Hz), 6.59 (d, 2H, J ) 8.3 Hz), 4.49 (d, 1H, J ) 17.5 Hz),
4.39 (d, 1H, J ) 17.5 Hz), 4.05 (t, 2H, J ) 4.6 Hz), 3.93 (d, 1H,
J ) 18.0 Hz), 3.83 (d, 1H, J ) 18.0 Hz), 3.74 (s, 3H), 3.72 (s,
3H), 3.51 (s, 1H), 3.26 (t, 1H, J ) 6.5 Hz), 1.84 (m, 1H), 1.73
(m, 1H), 1.49 (m, 1H), 1.47 (m, 1H), 1.13 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 179.2, 159.1, 158.9, 142.3, 138.9, 128.2,
127.9, 126.4, 126.2, 114.2, 113.9, 112.7, 112.3, 64.3, 59.2 (2C),
56.7, 54.9, 52.5, 41.9, 38.6, 27.8, 27.2 (3C), 26.1; LRMS (EI,
m/z, %): 424 (100) (M + H+), 338 (25), 280 (15), 258 (45), 165
(20); HRMS calculated for C26H34NO4 (M + H+) 424.551 03,
found 424.524 78.
give 27d (1.9 g, 89%) as a viscous oil: [R]20 +67.0° (c 1,
D
CHCl3); TLC Rf ) 0.38 (50% EtOAc in hexanes); 1H NMR (400
MHz, CDCl3) δ 7.20 (m, 4Η), 6.99 (m, 4Η), 3.74 (d, 2H, J )
13.3 Hz), 3.63 (t, 2H, J ) 6.3 Hz), 3.50 (m, 2H), 3.43 (d, 2H, J
) 13.3 Hz), 2.90 (bs, 1H, -OH), 2.78 (m, 1H), 1.83 (m, 1H),
1.52 (m, 3H), 1.32 (m, 1H); 13C NMR (100 MHz, C6D6) δ 160.8,
158.4, 132.9 (2C), 127.9 (4C); 112.7 (2C), 112.5 (2C), 59.3, 58.5,
56.1, 50.0 (2C), 27.4, 19.7; LRMS (EI, m/z, %) 336 (100) (M +
H+), 304 (30), 165 (10), 136 (40), 109 (80), 80.9 (15); HRMS
calcd for C19H22NO2F2 (M - H+) 334.161 87, found 334.162 90.
(4S)-2,2-Dim eth ylp r op ion ic Acid 4-Diben zyla m in o-5-
h yd r oxyp en tyl Ester (28a ). To a solution of diol 27a (11.2
g, 38.0 mmol) Et3N (5.67 mL, 41.0 mmol, 1.1 equiv) in
dichloromethane was treated with pivaloyl chloride (5.09 mL,
41 mmol, 1.1 equiv) dropwise at 0 °C. After 3 days at 0 °C,
water was added. The aqueous layer was extracted with CH2-
Cl2, and the combined organic layer was dried over Na2SO4
and evaporated. The residue was purified by flash chroma-
tography (hexane/ethyl acetate 7:3) to afford the desired
monopivaloyl ester 28a as a viscous oil (4.96 g, 32%): [R]D
+36.4° (c 1.0, CHCl3); TLC Rf ) 0.45 (20% EtOAc in hexanes);
1H NMR (400 MHz, CDCl3) δ 7.45-7.23 (m, 10H), 4.40 (t, 2H,
J ) 5.5 Hz), 3.82 (d, 2H, J ) 13.0 Hz), 3.52 (m, 2H), 3.44 (d,
2H, J ) 13.0 Hz), 3.10 (bs, 1H, -OH), 2.82 (m, 1H), 1.81 (m,
1H), 1.62 (m, 2H), 1.30 (m, 1H), 1.23 (s, 9H); 13C NMR (100
MHz, CDCl3) δ 278.9, 138.6 (2C), 129.4 (4C), 128.9 (4C), 127.7
(2C), 64.5, 61.2, 59.0, 53.7 (2C), 39.2, 27.7 (3C), 26.8, 22.0;
LRMS (EI, m/z, %) 384 (80) (M + H+), 352 (30), 132 (15), 91
(100); HRMS calculated for C24H34NO3 (M++1): 384.253 88,
found 384.252 70. An amount (6.5%) of the other regioisomeric
pivaloate was also obtained and separated.
(4S)-2,2-Dim eth ylp r op ion ic Acid 4-[Bis-(4-m eth oxy-
ben zyl)a m in o]-5-h yd r oxyp en tyl Ester (28b). By use of the
same procedure, 27b (12.3 g) was subjected to monopivaloy-
lation to give 28b (5.8 g, 38%) as a viscous oil: [R]D +32.1° (c
1.05, CHCl3); TLC Rf ) 0.40 (20% EtOAc in hexanes); 1H NMR
(400 MHz, CDCl3): δ 7.23 (d, 4H, J ) 8.0 Hz), 6.82 (d, 4H, J
) 8.5 Hz), 4.04 (t, 2H, J ) 6.5 Hz), 3.74 (s, 6H), 3.68 (d, 2H, J
) 13.0 Hz), 3.38 (m, 2H), 3.27 (d. 2H, J ) 13.0 Hz), 2.80 (bs,
1H, -OH), 2.74 (q, 1H, J ) 4.6 Hz), 1.79 (m, 2H), 1.52 (m,
2H), 1.18 (s, 9H); 13C NMR (100 MHz, CDCl3): δ 172.9, 159.2
(2 C), 131.6 (2C), 130.5 (4C), 114.3 (4C), 64.5, 61.1, 58.6, 55.6
(2C), 52.8 (2C), 39.2, 27.7 (3C), 26.8, 21.9; LRMS (FAB, NBA,
m/z, %) 444 (30) (M + H+), 412 (10), 121 (100); HRMS calcd
for C26H38NO5 (M + H+): 444.274 99, found 444.273 60.
(4S)-2,2-Dim eth ylp r op ion ic Acid 4-[Bis(4-br om oben -
zyl)a m in o]-5-h yd r oxyp en tyl Ester (28c). By use of the
same procedure, 27c (1.52 g) was subjected to monopivaloy-
lation to give 28c (0.57 g, 32%) as a viscous oil: [R]D +26.2° (c
1
1, CHCl3); TLC Rf ) 0.50 (20% EtOAc in hexanes); H NMR
(400 MHz, CDCl3) δ 7.41 (d, 4H, J ) 7.9 Hz), 7.10 (d, 4H, J )
8.6 Hz), 4.01 (t, 2H, J ) 6.5 Hz), 3.70 (d, 2H, J ) 17.5 Hz),
3.47 (m, 2H), 3.35 (d, 2H, J ) 17.5 Hz), 2.72 (q, 1H, J ) 4.5
Hz), 1.74 (m, 1H), 1.66 (m, 2H), 1.55 (m, 1H), 1.17 (s, 9H); 13
C
NMR (100 MHz, CDCl3) δ 178.9, 138.5 (2C), 132.4 (4C), 131.0
(4C), 121.8 (2C), 64.3, 61.3, 59.2, 53.1, 39.2, 27.6 (3C), 26.7,
22.1; LRMS (FAB, NBA, m/z, %) 542 (20) (M + H+), 510 (30),
169 (100), 147 (15), 91 (15).
(4S)-2,2-Dim eth ylp r op ion ic Acid 4-[Bis(4-flu or oben -
zyl)a m in o]-5-h yd r oxyp en tyl Ester (28d ). By use of the
same procedure, 27d (1.48 g) was subjected to monopivaloy-
lation to give 28d (2.09 g, 50%) as a viscous oil: [R]D +65.3° (c
(13S)-2,2-Dim eth ylp r op ion ic Acid 3-(2,10-Dibr om o-7,-
12-d ih yd r o-5H -6,12-m et h a n od ib en zo[c,f]a zocin -13-yl)-
p r op yl Ester (29c). By use of the same procedure, 28c (1.0
g) was subjected to Swern oxidation and Friedel-Crafts

Isopavines
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 1 45
reaction to give 29c (0.42 g, 45%) as a viscous oil: [R]D +15.1°
(c 1, CHCl3); TLC Rf ) 0.20 (50% EtOAc in hexanes); 1H NMR
(400 MHz, CDCl3) δ 7.31 (d, 2H, J ) 7.9 Hz), 7.15 (d, 2H, J )
8.0 Hz), 6.84 (t, 2H, J ) 6.9 Hz), 4.48 (d, 1H, J ) 18.0 Hz),
4.28 (d, 1H, J ) 18.0 Hz), 4.08 (m, 2H), 3.87 (d, 1H, J ) 17.5
Hz), 3.69 (d, 1H, J ) 18.0 Hz), 3.52 (s, 1H), 3.22 (t, 1H, J )
4.8 Hz), 1.78 (m, 1H), 1.59 (m, 1H), 1.52 (m, 1H), 1.34 (m, 1H),
1.08 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 178.9, 142.9, 140.0,
133.0, 132.7, 131.2, 130.9, 130.0, 129.9, 128.4, 128.0, 120.4,
120.2, 64.3, 59.6, 56.4, 52.3, 40.3, 39.1, 27.6, 27.5 (3C), 26.0;
HRMS calculated for C24H27NO2Br2 (M+) 521.290 83, found
521.284 36.
CDCl3) δ 142.8, 140.1, 132.2, 131.1, 130.9, 130.1, 129.5, 128.7,
128.5, 128.0, 125.8, 120.5, 63.6, 59.6, 57.6, 52.2, 41.9, 32.1, 31.0;
HRMS calculated for C19H19NOBr2 (M+) 437.173 24, found
437.165 41.
(13S)-3-(2,10-Diflu or o-7,12-d ih yd r o-5H-6,12-m eth a n od -
iben zo[c,f]a zocin -13-yl)p r op a n -1-ol (30d ). By use of the
above procedure, from 29d (450 mg), 30d (255 mg, 81%) was
obtained as a viscous oil: [R]D +52.7° (c 1, CHCl3); TLC Rf )
0.35 (5% MeOH in EtOAc); 1H NMR (400 MHz, CDCl3) δ 6.93
(m, 4H), 6.74 (m, 2H), 5.60 (bs, 1H), 4.50 (d, 1H, J ) 17.5 Hz),
4.46 (d, 1H, J ) 18.3 Hz), 3.95 (d, 1H, J ) 17.5 Hz), 3.83 (d,
1H, J ) 18.3 Hz), 3.72 (m, 1H), 3.52 (m, 2H), 3.27 (m, 1H),
1.70 (m, 3H), 1.49 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 161.0,
142.2, 139.3, 128.1, 128.0, 127.6, 127.2, 114.5, 113.8, 113.5,
113.3, 63.0, 58.8, 56.9, 51.4, 41.8, 31.5, 30.3; LRMS (EI, m/z,
%) 315 (100) (M+), 285 (80), 254 (30), 218 (60), 254 (20), 218
(13S)-2,2-Dim eth ylp r op ion ic Acid 3-(2,10-Diflu or o-7,-
12-d ih yd r o-5H -6,12-m et h a n od ib en zo[c,f]a zocin -13-yl)-
p r op yl Ester (29d ). By use of the same procedure, 28d (2.0
g) was subjected to Swern oxidation and Friedel-Crafts
reaction to give 29d (455 mg, 57%) as an amorphous solid:
(15), 206 (20), 163 (50), 147 (20); HRMS calculated for C19H19
-
NOF2 (M+) 315.143 47, found 315.143 65.
1
[R]D +24.6° (c 1, CHCl3); H NMR (400 MHz, CDCl3) δ 6.90
(m, 4H), 6.70 (m, 2H), 4.51 (d, 1H, J ) 17.5 Hz), 4.36 (d, 1H,
J ) 18.3 Hz), 4.05 (m, 2H), 3.94 (d, 1H, J ) 17.5 Hz), 3.76 (d,
1H, J ) 18.3 Hz), 3.52 (s, 1H), 3.23 (m, 1H), 1.85 (m, 1H),
1.76 (m, 1H), 1.53 (m, 1H), 1.42 (m, 1H), 1.10 (s, 9H); 13C NMR
(100 MHz, CDCl3) δ 178.2, 162.0 (2C), 142.5, 139.5, 129.3,
129.0, 127.4, 127.1, 114.3, 113.9, 113.3, 113.1, 63.8, 59.2, 55.8,
51.6, 40.4, 38.5, 27.2, 26.9 (3C), 25.5; LRMS (EI, m/z, %) 399
(80) (M+), 290 (70), 233 (30), 124 (20); HRMS calculated for
Steven s Rea r r a n gem en t. Typ ica l P r oced u r e for Iso-
p a vin e (32a ). To a solution of 30a (1.4 g, 5.0 mmol) in dry
benzene (20 mL) was added thionyl chloride (0.79 mL, 10.0
mmol, 2.0 equiv), and the mixture was refluxed for 1 h.
Evaporation of solvent gave the corresponding chloride in
quantitative yield as an amorphous solid. The chloride was
dissolved in dry 1,4-dioxane (20 mL), potassium tert-butoxide
(1.68 g, 15.0 mmol, 3 equiv) was added, and the mixture was
warmed to 80 °C. After 1 h, water was added and the aqueous
layer was extracted with dichloromethane. The combined
organic layers were washed with brine, dried over Na2SO4, and
concentrated in vacuo. The residue was purified by flash
chromatography to give pure 32a (0.98 g, 75%) as a white
solid: [R]D +180.1° (c 1, CHCl3); TLC Rf ) 0.40 (5% MeOH in
C
24H27NO2F2 (M+) 399.200 98, found 399.200 22.
(13S)-3-(7,12-Dih yd r o-5H -6,12-m et h a n od ib en zo[c,f]a -
zocin -13-yl)p r op a n -1-ol (30a ). To a solution of pivaloyl ester
29a (3.0 g, 8.2 mmol) in dry toluene (30 mL) was added
DIBAl-H solution (1.5 M in toluene, 16.4 mL, 24.5 mmol, 3.0
equiv) at -78 °C. The mixture was stirred for 1 h at - 78 °C.
Then methanol (3.5 mL) was added and the mixture was
warmed to room temperature. A saturated solution of potas-
sium and sodium tartrate tetrahydrate was added, and the
mixture was stirred for 30 min. The layers were separated,
and the aqueous phase was extracted with ethyl acetate. The
combined organic layers were washed with brine, dried over
Na2SO4, and concentrated in vacuo. The crude product was
purified by chromatography to give 30a (2.2 g, 99%) as a
viscous oil: [R]D +37.5° (c 1, CHCl3); 1H NMR (400 MHz,
CDCl3): δ 7.14-6.78 (m, 6H), 4.60 (d, 1H, J ) 17.6 Hz), 4.50
(d, 1H, J ) 18.5 Hz), 4.0 (d, 1H, J ) 17.6 Hz), 3.90 (d, 1H, J
) 18.5 Hz), 3.73 (dt, 1H, J ) 8.9, 4.4 Hz), 3.60 (s, 1H), 3.56
(dt, 1H, J ) 8.8, 3.2 Hz), 3.30 (dd, 1H, J ) 5.1, 3.3 Hz), 1.73-
1.60 (m, 3H), 1.52 (m, 1H); 13C NMR (100 MHz, CDCl3): δ
140.9, 138.0, 132.6, 132.5, 127.8, 127.6, 126.5, 126.4, 126.2,
126.1, 126.0, 125.6, 63.0, 59.4, 57.5, 52.0, 41.8, 31.7, 30.6;
1
EtOAc); H NMR (400 MHz, C6D6) δ 7.05-6.82 (m, 7H), 6.80
(m, 1H), 4.20 (dd, 1H, J ) 1.7, 4.6 Hz), 3.72 (ddd, 1H, J ) 3.0,
6.3, 9.5 Hz), 3.52 (d, 1H, J ) 3.0 Hz), 3.47 (dd, 1H, J ) 4.6,
17.8 Hz), 2.82 (dd, 1H, J ) 11.2, 7.2 Hz), 2.70 (ddd, 1H, J )
5.5, 8.1, 10.6 Hz), 2.64 (d, 1H, J ) 17.8 Hz), 1.73 (m, 1H), 1.62
(m, 1H), 1.50 (m, 1H), 1.22 (m, 1H); 13C NMR (100 MHz, C6D6)
δ 140.1, 138.7, 136.9, 132.9, 128.7, 127.6, 124.3, 124.1, 124.0,
123.1, 122.7 (2C), 61.7, 55.4, 50.5, 46.2, 33.3, 26.8, 24.1; LRMS
(EI, m/z, %) 261 (100) (M+), 192 (40); HRMS calculated for
C
19H19N (M+): 261.151 75, found 261.152 16.
Isop a vin e (32b). By use of the same procedure, 31b (570
mg) was subjected to Stevens rearrangement to give 32b (350
mg, 72%) as an amorphous solid: mp 118-120 °C; [R]20
D
+106.8° (c 1, CHCl3); TLC Rf ) 0.50 (10% MeOH in CHCl3);
1H NMR (400 MHz, C6D6) δ 7.23 (d, 1H, J ) 8.5 Hz), 6.94 (d,
1H, J ) 8.0 Hz), 6.76 (d, 1H, J ) 7.9 Hz), 6.72 (d, 1H, J ) 8.0
Hz), 6.64 (d, 1H, J ) 8.0 Hz), 6.62 (d, 1H, J ) 8.5 Hz), 4.56 (t,
1H, J ) 3.0 Hz), 3.96 (ddd, 1H, J ) 3.0, 6.3, 9.5 Hz), 3.77 (s,
3H), 3.74 (s, 3H), 3.68 (dd, 1H, J ) 3.5, 18.0 Hz), 3.36 (t, 1H,
J ) 6.5 Hz), 2.95 (dd, 1H, J ) 6.5, 13.0 Hz), 2.92 (m, 1H), 2.02
(m, 2H), 1.81 (m, 1H), 1.42 (m, 1H); 13C NMR (100 MHz, C6D6)
δ 159.3, 157.8, 141.6, 138.6, 132.0, 127.1, 124.8, 115.5, 112.7,
112.3, 111.4, 64.9, 57.5, 55.2 (2C), 51.0, 49.6, 34.2, 28.3, 25.7;
LRMS (EI, m/z, %) 279 (100) (M+); HRMS calculated for C19H21
-
NO (M+): 279.162 31, found 279.162 50.
(13S)-3-(2,10-Dim eth oxy-7,12-d ih yd r o-5H-6,12-m eth a -
n od iben zo[c,f]a zocin -13-yl)p r op a n -1-ol (30b). By use of
the above procedure, from 29b (0.72 g), 31b (0.573 g, 99%)
was obtained as a viscous oil: [R]D +37.7° (c 1.0, CHCl3); TLC
Rf ) 0.30 (5% MeOH in EtOAc); 1H NMR (400 MHz, CDCl3) δ
7.14 (2d, 2H, J ) 8.5 Hz), 6.88 (d, 1H, J ) 2.5 Hz), 6.79 (d,
1H, J ) 2.5 Hz), 6.64 (2dd, 2H, J ) 2.8, 8.0 Hz), 4.49 (d, 1H,
J ) 17.8 Hz), 4.40 (d, 1H, J ) 18.0 Hz), 4.13 (t, 1H, J ) 4.8
Hz), 3.94 (d, 1H, J ) 17.5 Hz), 3.82 (d, 1H, J ) 18.0 Hz), 3.72
(s, 3H), 3.70 (s, 3H), 3.57 (m, 2H), 3.50 (s, 1H), 3.20 (bs, 1H,
-OH), 1.76 (m, 2H), 1.32 (m, 2H); 13C NMR (100 MHz, CDCl3)
δ 157.9 (2C), 141.5 138.7, 127.1, 126.6, 123.8 (2C), 113.0, 112.7,
112.2, 111.9, 63.2, 58.7, 57.8 (2C), 55.1, 51.4, 42.6, 31.5, 30.8;
HRMS calculated for C21H25NO3 (M + H+) 339.433 42, found
339.418 24.
HRMS calculated for
321.172 00.
C
21H23NO2 321.172 87 (M+), found
Isop a vin e (32c). By use of the same procedure, 31c (75
mg) was subjected to Stevens rearrangement to give 32c (30
mg, 39%) as an amorphous solid: [R]D +155.2° (c 1, CHCl3);
TLC Rf ) 0.50 (10% MeOH in EtOAc); 1H NMR (400 MHz,
CDCl3) δ 7.46-7.08 (m, 6H), 4.91 (bs, 1H), 4.12 (m, 1H), 3.87
(s, 1H), 3.59 (m, 1H), 3.53 (d, 1H, J ) 18.0 Hz), 3.12 (d, 1H, J
) 17.8 Hz), 2.89 (q, 1H, J ) 3.0 Hz), 2.18 (m, 2H), 1.89 (m,
1H), 1.52 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 143.2, 140.3,
133.2 (2C), 130.8 (2C), 129.0 (2C), 127.9 (2C), 121.8, 120.4,
64.7, 57.7, 51.5, 49.4, 35.0, 29.3, 26.6; LRMS (FAB, NBA, m/z,
%) 419 (100) (M+), 340 (45); HRMS calculated for C19H17NBr2
(M+) 419.158 05, found 419.197 86.
(13S)-3-(2,10-Dibr om o-7,12-d ih yd r o-5H-6,12-m eth a n o-
d iben zo[c,f]a zocin -13-yl)p r op a n -1-ol (30c). By use of the
above procedure, from 29c (110 mg), 30c (76 mg, 87%) was
obtained as a viscous oil: [R]D +36° (c 1, CHCl3); TLC Rf )
1
0.40 (50% EtOAc in hexanes); H NMR (400 MHz, CDCl3) δ
Isop a vin e (32d ). By use of the same procedure, 31d (250
mg) was subjected to Stevens rearrangement to give 32d (119
mg, 80%) as an amorphous solid: [R]D +178° (c 1, CHCl3); TLC
7.40-6.82 (m, 6H), 4.42 (d, 1H, J ) 18.0 Hz), 4.36 (d, 1H, J )
18.5 Hz), 3.84 (d, 1H, J ) 17.8 Hz), 3.68 (d, 1H, J ) 17.6 Hz),
3.66 (m, 2H), 3.51 (s, 1H), 3.22 (d, 1H, J ) 10.0 Hz), 2.32 (bs,
1H, -OH), 1.76 (m, 2H), 1.38 (m, 2H); 13C NMR (100 MHz,
1
Rf ) 0.6 (10% MeOH in EtOAc); H NMR (400 MHz, C6D6) δ
7.30 (m, 1H), 6.85-6.50 (m, 5H), 4.07 (d, 1H, J ) 4.4 Hz), 3.54

46 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 1
Hanessian et al.
(ddd, 1H, J ) 3.1, 6.2, 9.4 Hz), 3.28 (dd, 1H, J ) 4.4, 17.9 Hz),
3.13 (d, 1H, J ) 3.1 Hz), 2.80 (dd, 1H, J ) 7.3, 13.8 Hz), 2.59
(ddd, 1H, J ) 5.5, 8.3 Hz), 2.40 (d, 1H, J ) 17.9 Hz), 1.69 (m,
1H), 1.45 (m, 2H), 1.01 (m, 1H); LRMS (EI, m/z, %) 297 (80)
(M+), 295 (60), 228 (15); HRMS calculated for C19H17NF2
(M+): 297.132 90, found 297.132 99.
Isop a vin e (33). Typical procedure described for 13 was
followed. From 32c (20 mg), 33 was obtained as a viscous oil
(105 mg, 48%): [R]D -38.1° (c 1, CHCl3); TLC Rf ) 0.26 (10%
MeOH in CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.12 (d, 1H, J
) 8.0 Hz), 6.81 (d, 1H, J ) 7.5 Hz), 6.34 (dd, 1H, J ) 3.0, 8.0
Hz), 6.31 (d, 1H, J ) 3.0 Hz), 4.43 (bs, 1H), 4.27 (s, 2H), 3.71
(m, 1H), 3.61 (s, 1H), 3.55 (d, 1H, J ) 18.0 Hz), 3.09 (t, 1H, J
) 3.0 Hz), 2.88 (m, 1H), 2.77 (d, 1H, J ) 18.0 Hz), 2.04 (m,
1H), 1.88 (m, 2H), 1.22 (m, 1H); 13C NMR (100 MHz, CDCl3)
δ 146.9, 139.5, 32.4, 130.4, 129.1 (4C), 128.9 (2C), 128.0 (4C),
127.8 (2C), 114.7, 112.6, 64.6, 58.0, 52.1, 49.4, 48.8, 34.5, 29.2,
26.7; LRMS (FAB, NBA, m/z, %) 445 (100) (M+), 375 (45), 284
(20), 154 (80), 136 (100); HRMS calcd for C26H25N2Br 445.400 96
(M+).
60.7, 58.8, 53.0 (2C), 32.7, 24.8, 23.3; LRMS (EI, m/z, %) 314
(80) (M + H+), 282 (30), 192 (65); HRMS calculated for C20H28
-
NO2 (M + H+) 314.212 00, found 314.211 71.
(5S)-2,2-Dim eth ylp r op ion ic Acid 5-Diben zyla m in o-6-
h yd r oxyh exyl Ester (36). Typical procedure described for
28a was followed. Monopivaloylation of 35 (1.39 g) gave 36 as
1
a viscous oil (1.98 g, 50%): [R]D +54.0° (c 1, CHCl3); H NMR
(400 MHz, CDCl3) δ 7.35-7.20 (m, 10H), 4.05 (t, 2H, J ) 7.3
Hz), 3.82 (d, 2H, J ) 13.5 Hz), 3.50 (m, 2H), 3.43 (d, 2H, J )
13.5 Hz), 2.79 (m, 1H), 1.75 (m, 1H), 1.62 (m, 2H), 1.30 (m,
3H), 1.22 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 178.4, 139.1
(2C), 128.9 (4C), 128.3 (4C), 127.1 (2C), 63.7, 60.6, 58.6, 53.1
(2C), 38.6, 28.7, 27.1 (3C), 24.6, 23.3; LRMS (EI, m/z, %) 398
(100) (M + H+), 320 (35), 276 (60), 240 920), 181 (15), 104 (40),
91 (80); HRMS calculated for C25H36NO3 (M + H+) 398.269 53,
found 398.268 40.
(13S)-2,2-Dim eth ylp r op ion ic Acid 4-(7,12-Dih yd r o-5H-
6,12-m et h a n od ib en zo[c,f]a zocin -13-yl)b u t yl E st er (37).
Typical procedure described for 29a was followed. A two-step
Swern oxidation and Friedel-Crafts cyclization on 36 (1.95
g) gave 37 as an amorphous solid (535 mg, 71%): [R]D +26.7°
Isop a vin e (34a ). Typical procedure described for 9 was
followed. A solution of 32b (100 mg) was refluxed at 120 °C
with 3.0 mL of aqueous HBr for 3 h to give 34a as a pale-
yellow solid (41 mg, 49%): mp 240-242 °C; [R]D +42° (c 1,
1
(c 1, CHCl3); H NMR (400 MHz, CDCl3) δ 7.20 (m, 2H), 7.10
(m, 4H), 6.95 (m, 2H), 4.63 (d, 1H, J ) 17.8 Hz), 4.47 (d, 1H,
J ) 18.5 Hz), 4.10-4.01 (m, 3H), 3.84 (d, 1H, J ) 18.4 Hz),
1
MeOH); TLC Rf ) 0.23 (30% MeOH in CHCl3); H NMR (400
3.65 (s, 1H), 3.31 (m, 1H), 1.70-1.40 (m, 6H), 1.20 (s, 9H); 13
C
MHz, MeOD) δ 7.21 (d, 1H, J ) 8.5 Hz), 6.87 (d, 1H, J ) 8.0
Hz), 6.74-6.40 (m, 4H), 4.56 (bs, 1H), 4.02 (dd, 2H, J ) 4.5,
17.7 Hz), 3.60 (d, 1H, J ) 17.0 Hz), 3.46 (q, 1H, J ) 4.8 Hz),
3.21 (s, 1H), 3.03 (d, 1H, J ) 16.8 Hz), 1.94 (m, 2H), 1.51 (q,
1H, J ) 4.6 Hz), 1.17 (m, 1H); 13C NMR (100 MHz, MeOD) δ
158.8, 156.4, 142.0, 137.9, 132.3, 128.0, 124.4, 122.5, 116.7,
115.4, 114.6, 113.2, 68.1, 60.0, 50.8, 32.8, 27.8, 25.5; HRMS
calcd for C19H19NO2 293.364 62 (M+), found 293.314 20.
Isop a vin e (34b). Typical procedure described for 11 was
followed. An amount of 34a (30 mg) was subjected to acety-
lation to give 34b as a viscous oil (31 mg, 89%): [R]D -18.3° (c
1, CHCl3); TLC Rf ) 0.50 (20% MeOH in EtOAc); 1H NMR
(400 MHz, CDCl3) δ 7.26 (d, 1H, J ) 8.0 Hz), 7.03 (d, 1H, J )
8.5 Hz), 6.92-6.72 (m, 4H), 4.45 (t, 1H, J ) 3.0 Hz), 3.78 (m,
2H), 3.72 (d, 1H, J ) 18.5 Hz), 3.12 (t, 1H, J ) 6.0 Hz), 2.94
(s, 1H), 2.90 (d, 1H, J ) 17.5 Hz), 2.27 (s, 3H), 2.25 (s, 3H),
1.82 (m, 2H), 1.24 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 169.8,
169.7, 150.3, 149.1, 142.7, 139.6, 132.5, 132.2, 127.2, 123.3,
120.7, 120.5, 119.2, 64.7, 57.7, 52.0, 49.4, 35.2, 29.3, 26.7, 21.6
(2C); HRMS calcd for C23H23NO4 377.439 04 (M)+, found
377.416 35.
NMR (100 MHz, CDCl3) δ 178.4, 141.4, 138.2, 134.0, 133.7,
128.0, 127.6, 126.2, 126.1, 126.0, 125.9, 125.8, 125.6, 64.1, 59.9,
56.7, 52.5, 40.3, 38.7, 30.7, 28.5, 27.1 (3C), 22.9; LRMS (EI,
m/z, %) 377 (M+) (100), 335 (35), 276 (40), 205 (60), 77 (15);
HRMS calculated for
377.234 59.
C
25H31NO2 (M+) 377.235 48, found
(13S)-4-(7,12-Dih yd r o-5H -6,12-m et h a n od ib en zo[c,f]a -
zocin -13-yl)bu ta n -1-ol (38). Typical procedure described for
30a was followed. From 37 (530 mg), 38 was obtained as a
1
viscous oil (235 mg, 81%): [R]D +29.7° (c 1, CHCl3); H NMR
(400 MHz, CDCl3) δ 7.23 (m, 2H), 7.08 (m, 4H), 6.97 (m, 2H),
4.60 (d, 1H, J ) 17.7 Hz), 4.46 (d, 1H, J ) 18.5 Hz), 4.02 (d,
1H, J ) 17.7 Hz), 3.83 (d, 1H, J ) 18.4 Hz), 3.63 (m, 3H), 3.45
(m, 1H), 2.55 (bs, 1H), 1.60 (m, 5H), 1.50 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ 141.3, 138.2, 133.7, 133.4, 128.0, 127.5,
126.3, 126.1, 126.0, 125.9, 125.8, 125.6, 62.5, 59.8, 56.7, 52.4,
40.3, 32.3, 30.8, 22.6; LRMS (EI, m/z, %) 293 (M+) (80), 202
(40); HRMS calculated for C20H23NO (M+) 293.177 96, found
293.178 29.
Isop a vin e (39). Typical procedure described for 31a was
followed. Rearrangement of 38 (230 mg) gave 39 as a viscous
oil (99 mg, 72%): [R]D -44.3° (c 1, CHCl3); 1H NMR (400 MHz,
C6D6) δ 7.15-6.88 (m, 8H), 3.71 (dd, 1H, J ) 2.2, 4.5 Hz), 3.50
(s, 1H), 3.39 (dd, 1H, J ) 2.2, 17.8 Hz), 2.91 (dd, 1H, J ) 2.2,
10.9 Hz), 2.82 (m, 1H), 2.72 (dd, 1H, J ) 4.5, 17.8 Hz), 2.62
(dt, 1H, J ) 3.1, 10.9 Hz), 1.73-1.40 (m, 5H), 1.23 (m, 1H);
13C NMR (100 MHz, C6D6) δ 144.4, 139.0, 138.7, 132.9, 128.7
(2C), 124.3, 124.0, 123.2, 123.1, 122.9, 121.3, 63.0, 60.5, 50.2,
49.6, 30.6, 29.3, 23.6, 22.9; LRMS (EI, m/z, %) 275 (80) (M+),
273 (20), 219 (15), 205 (40), 163 (25), 147 (60), 77 (40); HRMS
calculated for C20H21N (M+): 275.167 40, found 275.167 83.
(2S)-2-Diben zyla m in oh exa n e-1,6-d iol (35). To a solution
of L-2-aminoadipic acid (1 g, 6.2 mmol) in a 20% aqueous
solution of potassium carbonate (20 mL) was added benzyl
bromide (4.4 mL, 37 mmol, 6.0 equiv), and the mixture was
refluxed with stirring for 12 h. The aqueous layer was
extracted with EtOAc. The combined organic layers were
washed with brine, dried over Na2SO4, and concentrated in
vacuo. The residue was purified by flash chromatography
(hexane/EtOAc 80/20) to give crude dibenzyl diester (2.63 g,
1
81%) as an oil: [R]D -66.5° (c 1, CHCl3); H NMR (400 MHz,
CDCl3) δ 7.48-7.18 (m, 20H), 5.31 (d, 1H, J ) 12.2 Hz), 5.19
(d, 1H, J 12.4 Hz), 5.10 (s, 2H), 3.94 (d, 2H, J ) 13.8 Hz), 3.55
(d, 2H, J ) 13.8 Hz), 3.41 (dd, 1H, J ) 6.0, 8.8 Hz), 2.24 (t,
Biologica l Assa ys. Procedures described in ref 69 were
followed. In brief, human HEK-293S cells expressing the
human µ, δ, κ receptor were harvested and P2 membrane
preparations were produced. In receptor binding assays,
membranes were combined with test compounds (5 or 10
concentrations in duplicate per curve), ∼0.07 nM of the
appropriate radioligand [125I]-[D-Ala2]-deltorphin II (Kd ) 0.93
nM), [125I]-FK33824 (Kd ) 1.14 nM), and [125I]-D-Pro10-dynor-
phin A[1-11] (Kd ) 0.16 nM) in 50 mM Tris, 3 mM MgCl2, 1
mg/mL BSA, pH 7.4. The amounts of bound radioactivity were
determined at equilibrium by filtration. The nonspecific (NS)
binding was defined in the presence of 10 µM naloxone. The
IC50 values of test compounds were determined from two-
parameter logistic curve fits of the percentage of specific
binding vs log(molar ligand), solving for IC50 and hill slope.
Reference compounds showed expected IC50 values for the µ
(DAMGO IC50 ) 0.6 nM), δ (deltorphin II IC50 ) 1.3 nM), and
κ (U69593 IC50 ) 2.2 nM) receptors. In functional assays, GTP-
2H, J ) 7.2 Hz), 1.90 (m, 2H), 1.72 (m, 1H), 1.63 (m, 1H); 13
C
NMR (100 MHz, CDCl3) δ 172.9, 172.4, 139.3 (2C), 135.9 (2C),
128.7 (2C), 128.5 (2C), 128.4 (4C), 128.3 (4C), 128.2 (4C), 128.0
(2C), 126.9 (2C), 65.9 (2C), 60.0, 54.3 (2C), 33.5, 28.5, 21.4;
LRMS (EI, m/z, %) 522 (100) (M + H+), 446 (15), 386 (40), 296
(20), 181 (15), 91 (80), 77 (30); HRMS calculated for C34H36
-
NO4 (M + H+): 522.264 40, found 522.263 20.
The general procedure as described for 27a was followed.
From 2.63 g of dibenzylamino adipic diester subjected to LAH
reduction was obtained 35 as a yellow amorphous solid (1.39
g, 89%): [R]D +70.6° (c 0.77, CHCl3); 1H NMR (400 MHz, CDCl3)
δ 7.33-7.20 (m, 10H), 3.82 (d, 2H, J ) 13.2 Hz), 3.61 (m, 2H),
3.52 (m, 1H), 3.45 (m, 3H), 2.80 (m, 1H), 2.35 (bs, 1H), 1.75
(m, 1H), 1.53 (m, 2H), 1.30 (m, 3H); 13C NMR (100 MHz,
CDCl3) δ 128.9 (4C), 128.4 (4C), 128.3 (2C), 127.1 (2C), 62.2,

Isopavines
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 1 47
[γ]35S binding was used as an indicator of receptor/G-protein
activation. Membranes expressing hµ receptors (0.2 pmol/mg
protein) were combined with test compounds (10 concentra-
tions in duplicate per curve) and ∼0.2 nM GTP[γ]35S in 50 mM
Hepes, 20 mM NaOH, pH 7.4, 5 mM MgCl2, 100 mM NaCl, 1
mM EDTA, 1 mM DTT, 0.1% BSA, 15 µM GDP. The bound
radioactivity was determined after 1 h by filtration. Control
and stimulated binding were determined respectively in the
absence and presence of reference agonist (30 µM DAMGO).
Values of EC50 and Emax for ligands were obtained from three-
parameter logistic curve fits of the percentage of stimulated
GTP[γ]35S binding vs log(molar ligand), solving for EC50 and
hill slope, and % Emax DAMGO had an EC50 of 220 nM.
(19) Beckett, A. H.; Casy, A. F. Synthetic Analgesics: Stereochemical
Considerations. J . Pharma: Pharmacol. 1954, 6, 986-1001.
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Deecher, D. C.; Bidlack, J . M. Asymmetric Synthesis, Opioid
Receptor Affinities, and Antinociceptive Effects of 8-Amino-5,9-
methanobenzo Cyclooctenes, a New Class of Structural Ana-
logues of the Morphine Alkaloids. J . Med. Chem. 1996, 39, 1956-
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(21) Wentland, M. P.; Duan, W.; Cohen, D. J .; Bidlack, J . M. Selective
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phine Derivatives. J . Med. Chem. 2000, 43, 3558-3565.
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Catalyzed Elaboration of Codeine and Morphine. J . Chem. Soc.,
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Ack n ow led gm en t. We thank the NSERC of Canada
for financial assistance through the Medicinal Chem-
istry Chair Program. We gratefully acknowledge helpful
discussions with Dr. Christopher Walpole, AstraZeneca
R&D. We thank Angelo Filosa (AstraZeneca R&D,
St-Laurent, Quebec) for the LC/MS analyses.
Su p p or tin g In for m a tion Ava ila ble: Selected HRMS
data, 1H NMR and 13C NMR spectra, and X-ray structure data
of the compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
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