Synthesis and inotropic activity of 1-(O-aminoalkyloximes) of perhydroindene derivatives as simplified digitalis-like compounds acting on the Na+,K+-ATpase

Article abstract of DOI:10.1021/jm011001k

A series of 5-substituted (3aS,7aR)-7a-methylperhydroinden-3a-o1 derivatives bearing a 1(S)-(ω-aminoalkoxy)iminoalkyl or -alkenyl substituent was synthesized, starting from the Hajos-Parrish ketol 47, as simplified analogues of very potent 17β-aminoalkylo

Full text of DOI:10.1021/jm011001k

J . Med. Chem. 2002, 45, 189-207
189
Syn th esis a n d In otr op ic Activity of 1-(O-Am in oa lk yloxim es) of P er h yd r oin d en e
Der iva tives a s Sim p lified Digita lis-lik e Com p ou n d s Actin g on th e
Na +,K+-ATP a se
Alberto Cerri,*,† Nicoletta Almirante,† Paolo Barassi,‡ Alessandra Benicchio,† Sergio De Munari,†
Giuseppe Marazzi,† Isabella Molinari,‡ Fulvio Serra,‡ and Piero Melloni†
Departments of Medicinal Chemistry and Cardiovascular Pharmacology, Prassis Istituto di Ricerche Sigma-Tau,
Via Forlanini 3, 20019 Settimo Milanese (MI), Italy
Received J uly 30, 2001
A series of 5-substituted (3aS,7aR)-7a-methylperhydroinden-3a-ol derivatives bearing a 1(S)-
(ω-aminoalkoxy)iminoalkyl or -alkenyl substituent was synthesized, starting from the Hajos-
Parrish ketol 47, as simplified analogues of very potent 17â-aminoalkyloximes with digitalis
skeleton, previously reported. The target compounds were evaluated in vitro for displacement
of the specific [3H]ouabain binding from the dog kidney Na+,K+-ATPase receptor. Some of them
revealed IC50 values in the micromolar range. The most active compounds possess a cyclohexyl
group in the 5(S) position and in position 1(S) the same aminoalkyloxime groups already
reported for the digitoxigenin-like series in position 17â. Although the ring conformation of
these derivatives was comparable to that of uzarigenin, the binding affinities of the most active
ones were 4/8-fold lower in comparison to that standard. Three compounds among those with
the highest affinities were assayed in vitro for their inotropic activity on an electrically driven
guinea pig left atrium and were found to be less potent than both digoxin, the most widely
used inotropic agent, and the corresponding digitalis 17â-aminoalkyloximes.
Ch a r t 1
In tr od u ction
Digitalis cardiac glycosides are drugs clinically used
for the treatment of congestive heart failure, although
their major problem is the low therapeutic index due
to cardiac pro-arrhythmogenic activity.1 Among them,
digoxin (Chart 1) is the most widely used one. Many
efforts have been made to find a safer cardiotonic agent,2
and our group has been involved (in the last years) in
the search for such a positive inotropic agent acting
through the inhibition of Na+,K+-ATPase.3-5
In the past, several attempts were made to replace
the steroidal digitalis skeleton with completely different
structures, such as deoxybenzoin,6 flavone,6 stilbene,6
indoline,7 isoquinoline,8 benzobicyclo[2,2,2]octane,9 with-
out obtaining favorable pharmacological results. More
recently, San Feliciano et al. reported some compounds
structurally derived from a simplification of the steroi-
dal skeleton: diterpene derivatives,10 in which the
D-ring was missing, and cyclohexane derivatives,11,12
maintaining only the C-ring, both linked to the buteno-
lide ring typically present in digitalis compounds. These
compounds did not show any positive inotropic activity.
In the same period, we also started working on
simplification of the digitalis skeleton, such as seco-D
compounds13 and perhydroindene derivatives,14 in order
to find the minimum structural requirements for the
recognition of the digitalis receptor and, possibly, a safer
inotropic agent. Recently, we published the synthesis
* Corresponding author: Alberto Cerri, Department of Medicinal
Chemistry, Prassis Istituto di Ricerche Sigma-tau, Via Forlanini, 3,
20019 Settimo Milanese (MI), Italy. Tel: 0039.0233500388. Fax:
0039.0233500408. E-mail: pstchem@tin.it.
of the butenolide derivative with a hydrindane skeleton
1 (Chart 1), which preserved the most distinctive part
of the digitalis skeleton, i.e., the C- and D-rings with a
† Department of Medicinal Chemistry.
‡ Department of Cardiovascular Pharmacology.
10.1021/jm011001k CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/22/2001

190 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 1
Cerri et al.
Ch a r t 2
Sch em e 1a
a
Reagents and conditions: compounds 2-11, 15-33, 35-38,
45, 46: H2NOR′′‚xHCl, NaOAc, HCl, dioxane, H2O, pH 4.5;
compounds 12, 34, 43, 44: H2NHC(NH)NH2‚H2CO3, dioxane, H2O,
HCl; compounds 39-42: H2NOR′′‚xHCl, NaOH, dioxane.
cis juntion; this compound showed a weak affinity to
the Na+,K+-ATPase receptor.15 In the same years, we
prepared some 17â-aminoalkyloxime derivatives of the
digitalis skeleton (Chart 2) showing particularly high
inhibitory activity on Na+,K+-ATPase and high inotropic
potency on guinea pig atrium; the most active com-
pounds were more potent than digoxin itself.16 The idea
that the replacement of the butenolide ring in compound
1 with the powerful activity inducing aminoalkyloxime
chain could enhance the potency of the hydrindane
derivatives brought us to prepare the derivatives de-
scribed in the present article.17 In the same period, San
Feliciano’s group published some other hydrindane
derivatives acting as inotropic agents:18,19 a recent paper
has been published as a compendium of their work.20
Sch em e 2a
a
Reagents and conditions: NaBH3CN, MeOH, H2O, HCl,
pH 3.
Ch em istr y
of 1-epimeric compounds 49 and 50, which could be
easily separated by flash chromatography. Careful
hydrolysis of ketal 49 gave the desired synthon 51
together with a small amount of the 3a,4 unsaturated
ketone. The undesired epimeric compound 50 could be
partially recovered to the useful derivative 49 by IBX
oxidation22 to the corresponding aldehyde 52 which was
converted in basic medium to a mixture of the 1-epimers
52 and 53, the latter being the more stable epimer,
followed by in situ NaBH4 reduction to a 2/1 mixture of
alcohols 49 and 50.
The 5-unsubstituted aldehyde 56 (Scheme 4) was
obtained by thioketalization of keto alcohol 51 followed
by Raney-Ni reduction of 54; IBX oxidation of the
5-unsubstituted alcohol 55 gave the desired aldehyde
56.
The preparations of the 5-benzylydene 59 (E) and 60
(Z), benzyl 63 (R) and 64 (S), and cyclohexylmethyl 66
(R) and 68 (S) aldehydes are described in Scheme 5.
Wittig reaction on ketol 51 gave approximately a 1:1
E/Z mixture of benzylidene derivatives 57 and 58 which
could be separated only partially. The purified com-
pounds were oxidized to aldehydes 59 and 60. Hydro-
genation of the mixture of 57 and 58 over Pd/C gave
the epimeric mixture of (5S) and (5R) benzyl derivatives
that could be chromatographically separated only by
transformation into the corresponding TBDMS ethers
61 and 62. Hydrolysis of the silyl group and oxidation
of the alcohols gave aldehydes 63 and 64. Hydrogenation
of pure 61 and 62, on Rh/Al2O3 at 4.3 atm, followed by
hydrolysis of the silyl group gave the cyclohexyl alcohols
65 and 67, which were oxidized, respectively, to the
aldehydes 66 and 68.
The synthetic pathways for the compounds listed in
Table 1 are reported in Schemes 1-11.
The oximes or guanylhydrazones 2-12 and 15-46
were synthesized from the corresponding aldehydes and
appropriate (O-substituted)hydroxylamines or amino-
guanidine according to general Scheme 1. Hydroxyl-
amines 13 and 14 were prepared by reduction of the
corresponding oximes 10 and 11 with NaBH3CN (Scheme
2).
The oximes and guanylhydrazones reported in Table
1 were obtained as pure or almost pure E isomers (Z
isomer ) 10%) except for compounds 35 (50% of Z
oxime), 36 (25% of Z oxime), 37 and 38 (20% of Z oxime).
Analogously to the corresponding digitalis-like oximes,16
compounds 2-12, 15-34 showed no E/Z isomerization
in D2O/DMSO-d6 solution at pH 7.4 (phosphate buffer)
and 37 °C (1H NMR analysis), while vinylic oximes 39-
40 gave a 6/4 E/Z equilibrium mixture, after 24 h.
Compounds 41 and 42, with a methyl group on the
double bond, were synthesized to stabilize the E isomer
and prevent isomerization.
The common synthon for all the described compounds
was the 1(S)-hydroxymethyl derivative 51 (Scheme 3)
susceptible of nucleophilic attack to the 5-keto group
with the appropriate reagent. Starting material was the
Hajos-Parrish ketol21 47 which shows the stereochem-
istry and substitutions at the quaternary carbon atoms
corresponding exactly to those of the digitalis C-D-
rings. The sequence from 47 to 51 (Scheme 3) was the
same described by Sevillano et al.20 although the reac-
tions were carried out in different conditions. Selective
protection of the 5-keto group as dioxolane with excess
of ethylene glycol and oxalic acid followed by Wittig
reaction on the 1-keto group gave the exomethylenic
compound 48; hydroboration of 48 yielded a 5/2 mixture
The introduction of a phenyl group in position 5R or
5â was accomplished by stereospecific â addition of

1-(O-Aminoalkyloximes) of Perhydroindene Derivatives
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 1 191
Ta ble 1. Structure, Analytical Data, and Na+,K+-ATPase Binding of Compounds 2-46
Na+,K+-ATPase
compd
R5
R1
mol formulaa
binding, IC50,b µM
1
2
3
4
5
6
7
8
>10c
>100e
50
d
H
(E) CHdNO(CH2)3NH2
(E) CHdNO(CH2)2N(CH3)2
(E) CHdNO(CH2)2N(CH3)2
(E) CHdNO(CH2)2N(CH3)2
(E) CHdNO(CH2)2N(CH3)2
(E) CHdNO(CH2)2N(CH3)2
(E) CHdNO(CH2)2N(CH3)2
(E) CHdNO(CH2)2N(CH3)2
(E) CHdNO(CH2)2N(CH3)2
(E) CHdNO(CH2)2NH2
(E) CHdNNdC(NH2)2
C14H26N2O2‚C2H2O4
(E) dCHC6H5
(Z) dCHC6H5
R-CH2C6H5
R-CH2C6H11
â-CH2C6H5
C22H32N2O2
C22H32N2O2
8.0
d
C22H34N2O2‚C2H2O4
>100f
100
3.2
C22H40N2O2
C22H34N2O2
C22H40N2O2
â-CH2C6H11
R-C6H5
4.0
d
9
C21H32N2O2‚C2H2O4
>100g
3.2
d
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
â-C6H5
C21H32N2O2‚C2H2O4
â-C6H5
C19H28N2O2
4.0
â-C6H5
C18H26N4O‚HCl
>100h
10
â-C6H5
CH2NHO(CH2)2N(CH3)2
CH2NHO(CH2)2NH2
C21H34N2O2‚C2H2O4d‚1.5H2O
d
â-C6H5
C19H30N2O2‚C2H2O4
C22H34N2O2
C20H30N2O2‚C2H2O4
C22H34N2O2
20
5.0
3.2
10
6.3
10
2.5
5.0
2.5
8.0
2.5
1.0
13
2.5
1.6
3.2
10
1.0
0.8
13
63
1.6
1.6
5.0
3.2
1.0
1.0
2.0
â-(3-H3CC6H4)
â-(3-H3CC6H4)
â-(4-H3CC6H4)
â-(4-H3CC6H4)
â-(3-HOC6H4)
â-(4-HOC6H4)
â-(3-HOCH2C6H4)
â-(3-HOCH2C6H4)
â-(4-HOCH2C6H4)
â-(4-HOCH2C6H4)
(E) CHdNO(CH2)2N(CH3)2
(E) CHdNO(CH2)2NH2
(E) CHdNO(CH2)2N(CH3)2
(E) CHdNO(CH2)2NH2
(E) CHdNO(CH2)2N(CH3)2
(E) CHdNO(CH2)2N(CH3)2
(E) CHdNO(CH2)2N(CH3)2
(E) CHdNO(CH2)2NH2
(E) CHdNO(CH2)2N(CH3)2
(E) CHdNO(CH2)2NH2
d
C20H30N2O2‚C2H2O4d‚0.33H2O
C21H32N2O3
C21H32N2O3‚0.2H2O
C22H34N2O3‚0.5H2O
C20H30N2O3‚C2H2O4d‚0.5H2O
C22H34N2O3
C20H30N2O3‚0.5H2O
C25H41N3O3
C20H31N3O2
â-(4-(H3C)2N(CH2)2OC6H4) (E) CHdNO(CH2)2N(CH3)2
â-(3-C5H4N)
â-(4-C5H4N)
â-C6H11
(E) CHdNO(CH2)2N(CH3)2
(E) CHdNO(CH2)2N(CH3)2
(E) CHdNO(CH2)2N(CH3)2
(E) CHdNO(CH2)3N(CH3)2
(E) CHdNO(CH2)4N(CH3)2
(E) CHdNO(CH2)2NH2
(E) CHdNO(CH2)3NH2
(E) CHdNO(CH2)4NH2
(E) CHdNNdC(NH2)2
(EZ) CH2CHdNO(CH2)2N(CH3)2
(EZ) CH2CHdNO(CH2)2NH2
(EZ) (CH2)2CHdNO(CH2)2N(CH3)2
(EZ) (CH2)2CHdNO(CH2)2NH2
(E,E) CHdCHCHdNO(CH2)2N(CH3)2
(E,E) CHdCHCHdNO(CH2)2NH2
C20H31N3O2‚0.33H2O
C21H38N2O2
C22H40N2O2‚C2H2O4
d
â-C6H11
â-C6H11
C23H42N2O2‚0.33H2O
d
â-C6H11
C19H34N2O2‚C2H2O4
â-C6H11
C20H36N2O2‚0.25H2O
d
â-C6H11
C21H38N2O2‚C2H2O4
â-C6H11
C18H32N4O‚1H2O
d
â-C6H11
C22H40N2O2‚C2H2O4
â-C6H11
C20H36N2O2
d
â-C6H11
C23H42N2O2‚C2H2O4
â-C6H11
C21H38N2O2‚0.5C2H2O4d‚1H2O
d
â-C6H11
C25H42N2O6‚C2H2O4
C21H36N2O2‚C2H2O4
d
â-C6H11
d
â-C6H11
(E,E) CHdC(CH3)CHdNO(CH2)2N(CH3)2 C24H42N2O2‚C2H2O4
d
â-C6H11
(E,E) CHdC(CH3)CHdNO(CH2)2NH2
(E,E) CHdCHCHdNNdC(NH2)2
(E,E) CHdC(CH3)CHdNNdC(NH2)2
(E) CHdNO(CH2)2N(CH3)2
C22H38N2O2‚C2H2O4
C20H34N4O‚1H2O
C21H36N4O‚HCl
C21H38NO3
1.3
â-C6H11
16
â-C6H11
>100g
1.6
â-(cis-4-HOC6H10
)
â-(trans-4-HOC6H10
)
(E) CHdNO(CH2)2N(CH3)2
C21H38NO3
1.0
116
117
118
digitoxigenin
uzarigenin
0.04
0.025
0.016
0.063
0.25
a
b
Analyses for C, H, N, Cl, and H2O are within 0.4% of the theoretical values. Concentrations able to displace 50% of the specific
[3H]ouabain binding. Mean of two or three experiments. c 30% displacement at 10 µM. Oxalate. e 20% displacement at 100 µM. f 45%
displacement at 100 µM. 30% displacement at 100 µM. 35% displacement at 100 µM.
d
g
h
phenyllithium to the synthon 51 (Scheme 6) and stereo-
selective hydrogenolysis of 69 with retention or inver-
sion of configuration. Hydrogenolysis over Pd/C in the
presence of HClO4 gave a 70/72 mixture in 3/1 ratio (the
main product showing inversion of configuration) which
could be separated by transforming the primary alcohols
into their TBDMS ethers. Once separated, the silyl
group of the main component was removed, affording
70 again which was oxidized to the aldehyde 71. The
more desired (5S)-phenyl derivative 72 was better
obtained from 69 by Raney-Ni stereospecific hydro-
genolysis in 82% yield, with retention of configuration.
The hydrogenation of the aromatic ring of 72 was
carried out over Rh/Al2O3 at 4.3 atm. IBX oxidation of
72 and 74 gave, respectively, 73 and 75.
The stereochemistry of the new stereocenter and the
conformation of the ring system in compounds 70 and
72 could be attributed on the basis of the NMR spectra.
In fact, in the derivative 72 the chemical shift of the
7a-methyl is 14.9 ppm (13C NMR) as in the correspond-
ing 17â-hydroxymethyl derivative with digitalis skeleton
(C-18 at 15.3 ppm),23 while in the case of 70 the

192 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 1
Cerri et al.
Sch em e 3a
a
Reagents and conditions: (a) (COOH)2, (CH2OH)2, MeCN; (b) CH3P(C6H5)3Br, t-BuOK, t-BuOH, THF, reflux, 2 h; (c) 1 M BH3, THF;
(d) H2O, NaBO3, 4 N NaOH; (e) 1 N pTSA, MeCN, H2O; (f) IBX, THF, reflux, 1 h; (g) 1.4 M KOH, MeOH; (h) NaBH4, -20 °C, 2.5 h.
Sch em e 4a
The aromatic aminoether 99 (Scheme 9) was obtained
by selective etherification of phenol 98 with 2-chloro-
ethyl-N,N-dimethylamine and Ag2CO3; oxidation of
compound 99 gave the 1S aldehyde 100 which was used
rapidly as crude material in order to avoid its partial
epimerization to the 1R epimer due to the presence of
the basic amine.
Homologation of the aldehyde 75 (Scheme 10) was
accomplished through the vinyl derivative 101, hydro-
boration to 102, and oxidation to the aldehyde which
proved to exist as lactol 103. Vinylogous aldehydes 105
and 108 (Scheme 10) were obtained by Horner-
Emmons reactions of 75 with the appropriate phos-
phonoacetates to give the esters 104 and 107, which
were reduced with DIBAH to the corresponding allylic
alcohols and oxidized to the aldehydes 105 and 108 with
MnO2. The saturated aldehyde 106 was obtained by
hydrogenation of 105 over Pd/C.
The TBDMS ethers of epimeric cyclohexanols 110 and
115 were obtained as reported in Scheme 11. Hydro-
genation of the aromatic ring of 93 over Rh/Al2O3 gave
the cis isomer 109 which was oxidized to the aldehyde
110. The epimeric trans isomer 115 was obtained by
first transforming the 1S hydroxymethyl derivative 109
into the corresponding acetate 111. Acidic hydrolysis
deprotection of the silyl ether and subsequent oxidation
gave the ketone 112. LiAlH(OtBut)3 reduction gave
selectively the axial alcohol 113 (only 10% of the
equatorial isomer) which was protected as TBDMS ether
114. Basic hydrolysis of the acetate followed by oxida-
tion of the resulting alcohol gave the aldehyde 115.
All the silyl ethers were deprotected in situ in acidic
conditions before the reaction with 2-dimethylamino-
ethoxyamine at the appropriate pH.
a
Reagents and conditions: (a) HSCH2CH2SH, CH2Cl2, BF3‚Et2O;
(b) Raney-Ni, EtOH, reflux, 16 h; (c) IBX, THF, reflux, 2.5 h.
corresponding chemical shift is downfield, 19.4 ppm,
diagnostic of a non-digitalis-like conformation (Figure
1). Since the hydrindane skeleton conformation is
controlled by the substituent in position 5 which must
be always in equatorial conformation (as confirmed by
MM2 calculations), the isomer in digitalis-like confor-
mation 72 has the 5â-phenyl group (Figure 1, digitalis-
like) while 70 has the 5R-phenyl. As a confirmation of
the digitalis-like conformation of 72, the multiplets of
1
the benzylic protons in the H NMR spectra of 70 and
72 at 2.83 and 2.73 ppm, respectively, suggest axial
conformations (Wh/2 ) 25 Hz) in both cases and, as a
consequence, the equatorial position of phenyls.
Compounds 76 and 77 (Scheme 7) were prepared, in
the same way, by stereospecific addition of the corre-
sponding aryllithium derivatives to the ketone 51.
Hydrogenolysis over Raney-Ni provided the desired silyl
ethers 80 and 81 along with the products of further
hydrogenolysis of the benzyl silyl ether to the methyl
derivatives 78 and 79. Again, oxidation of the alcohols
78-81 gave the aldehydes 82-85, respectively.
The same sequence, nucleophilic attack of the proper
aryllithium derivative to 51, hydrogenolysis over Raney-
Ni of 86-89, and oxidation of the alcohols 90-93, gave
the aldehydes 94-97 (Scheme 8).
Biologica l Activity
All compounds were evaluated in vitro for displace-
ment of the specific [3H]ouabain binding from the dog
kidney Na+,K+-ATPase receptor;24,25 data are shown in
Table 1. Compounds 28, 39, and 40 were chosen among
those with the highest affinities, to further investigate

1-(O-Aminoalkyloximes) of Perhydroindene Derivatives
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 1 193
Sch em e 5a
a
Reagents and conditions: (a) C6H5CH2P(C6H5)3Br, NaNH2, THF; (b) IBX, DMSO; (c) H2, 10% Pd/C, EtOAc; (d) TBDMSCl, imidazole,
DMF; (e) 3 N HCl, dioxane, H2O, pH 1; (f) H2, 5% Rh/Al2O3, MeOH, 4.3 atm.
Sch em e 6a
a
Reagents and conditions: (a) PhLi, THF, -78 °C, 1 h; (b) H2, 5% Pd/C, HClO4, EtOAc; (c) TBDMSCl, imidazole, DMF; (d) 3 N HCl,
dioxane, H2O, pH 1; (e) IBX, DMSO; (f) Raney-Ni, EtOH, reflux, 3 h; (g) H2, 5% Rh/Al2O3, MeOH, 4.3 atm.
in vitro their inotropic activity by measuring the effects
on the contractile force of an electrically driven guinea
pig left atrium;16 data are shown in Table 2.
As reference compounds, digoxin was chosen as the
most commonly prescribed cardiac glycoside in the
congestive heart failure, digitoxigenin and uzarigenin
were taken as models for their aglyconic digitalis
skeleton, and oximes 116-118 are examples of the
potent aminoalkyloximes previously reported (Chart
2).16

194 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 1
Cerri et al.
Sch em e 7a
a
Reagents and conditions: (a) 3- or 4-TBDMSOCH2C6H4Br, 1.6 M n-BuLi, THF, Et2O, -78 °C, 1.5 h; (b) Raney-Ni, EtOH, reflux, 3
days; (c) IBX, DMSO.
Sch em e 8a
F igu r e 1. Conformations of epimeric 5-substituted perhydro-
indene derivatives.
a
Reagents and conditions: (a) RBr, 1.6 M n-BuLi or 1.5 M
t-BuLi, Et2O or n-hexane or pentane, THF, -78 °C, 0.5 or 1.5 h;
(b) Raney-Ni, EtOH, reflux, 8 h; (c) IBX, DMSO or IBX, THF,
reflux, 1.5 h.
Resu lts a n d Discu ssion
The compounds were tested as pure compounds or
E/ Z isomeric mixtures of the iminic double bond when
they could not be obtained as pure isomers from the
synthesis and any attempt to separate them was
unproductive. The biological assays were performed
within 1-4 h from the dissolution of the compounds.
Since these compounds take a long time to equilibrate
at pH 7.4, as reported above, we assume that no
important isomerization occurred to the mixtures in the
biological systems used.
All the following reasoning is based on the mixtures
of components when they were used as such.
Bin d in g to th e Na +,K+-ATP a se. The structure-
activity relationships can be more easily discussed by
separating the observations on substituents in positions
5 and 1 of the perhydroindene skeleton.
possibly superimpose to the A ring of a steroidal
skeleton.
The most striking difference in affinities was afforded
by the comparison between 5R and 5â derivatives. 5R-
Substituted compounds 5, 6, and 9 were 25-30 times
less active than the corresponding 5â derivatives 7, 8,
and 10. The reason can be found in the different
conformations of the two epimeric series. As previously
shown in Figure 1, all perhydroindene derivatives have
their minimum conformational energy with the 5 sub-
stituents in equatorial position, and this results in
different conformations for the two epimeric hydrindane
derivatives (Figure 1). The 5R-substituted perhydro-
indenes present a non-digitalis-like conformation of the
CD rings, while the 5â substituted compounds are in
the digitalis-like conformation, which is most probably
the reason of their higher affinity to the receptor. As
previously described for the synthetic intermediates 70
and 72, such conformations have been demonstrated on
the basis of the NMR spectra. In the 5â-substituted
derivative 10, the 13C chemical shift of the 7a-methyl
is 15.7 ppm as in the corresponding 17â-aminoalkoxy-
P osition 5. The unsubstituted compound 2 showed
a very low affinity; this means that the perhydroindenic
skeleton itself does not afford a sufficient recognition
with the receptor.
As a consequence, our approach was directed toward
the addition of a substituent in position 5 that could

1-(O-Aminoalkyloximes) of Perhydroindene Derivatives
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 1 195
Sch em e 9a
marginally. A tentative explanation is that orientation
of the phenyl ring differs with respect to the A ring of
digitalis compounds and, as a consequence, also the
hydroxy groups point toward different directions. Note-
worthy was the aminoether 25 with a 3-fold higher
affinity in comparison with the unsubstituted analogue
10; the aminoether chain of 25 with a more flexible
conformation could probably reach the supposed sites
for hydrogen bonding corresponding to the oxygen atoms
of the sugars of the digitalis glycosides.
Substitution of the phenyl ring with a cyclohexyl gave
2/4-fold higher affinities: 28, 31, and 34 vs 10, 11, and
12, respectively. The cyclohexyl ring could better mimic
the A ring of steroids, even though a superimposition
to uzarigenin instead of digitoxigenin is more probable
(Figure 2). Surprisingly enough, also in this case, the
introduction of a hydroxy group in the position 4 of the
cyclohexyl ring, mimicking the 3-hydroxy substituent
of the digitalis compounds, as in compounds 45 and 46,
was not shown to be very effective. The affinity was
slightly improved only in the case of 46 where the 4â-
hydroxy substituent resembles better the spatial ar-
rangement of uzarigenin (Figure 2). A higher degree of
conformational freedom could explain the 4-fold lower
affinity of 46 in comparison with uzarigenin.
a
Reagents and conditions: (a) 3 N HCl, dioxane, H2O, pH 0.9;
(b) Ag2CO3, (Me)2NCH2CH2Cl, 50 °C, 6 h; (c) IBX, THF, reflux, 1
h.
imino derivative with digitalis skeleton (C-18 at 15.7
ppm),16 while in the 5R-substituted derivative 9 the
corresponding signal is downfield at 18.5 ppm. Further
evidence is the multiplets of the benzylic protons in the
1H NMR spectra of 9 and 10, at 2.81 and 2.70 ppm,
respectively, in both cases indicating an axial conforma-
tion (Wh/2 ) 25 Hz).
Since also the olefinic compounds 3 and 4 showed
affinities between those of the 5R and 5â derivatives 5
and 7, we focused our attention on the 5â substituted
hydrindanes.
Introduction of a substituent into the phenyl ring gave
results difficult to rationalize. Lipophilic or hydrophilic
substituents did not substantially change affinity. Also,
the introduction of a hydroxy group (compounds 19-
24), to mimic the 3-hydroxy substituent of the digitalis
skeleton, increased little the affinity occasionally and
P osition 1. The highest affinities could be found in
simple oximes with primary amines 31 and 32 and
vinylic oximes 39 and 40. The 6-7 bond distance
between the basic nitrogen and the hydrindane skeleton
in the simple oximes 31 and 32 or the presence of an
R,â-unsaturated system, resembling that of the digitalis
lactone, in compounds 39 and 40 were singled out as
characteristics productive of good affinity. The introduc-
tion of an R-methyl in the unsaturated oxime to stabilize
the E configuration, compounds 41 and 42, afforded a
slightly lower affinity, perhaps due to some steric
hindrance in the interaction with the receptor.
Sch em e 10a
a
Reagents and conditions: (a) CH3P(C6H5)3Br, t-BuOH, t-BuOK, THF; (b) 1 M BH3, THF, H2O, NaBO3, 4 N NaOH; (c) IBX, DMSO;
(d) 55% NaH, (CH3O)2P(O)CH2CO2CH3, THF; (e) 1 M DIBAH, THF, from -78 °C to room temperature; (f) MnO2, dioxane; (g) 5% Pd/C,
H2, EtOH, (h) 55% NaH, (C2H5O)2P(O)CH(CH3)CO2C2H5, THF.

196 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 1
Cerri et al.
Sch em e 11a
a
Reagents and conditions: (a) H2, 5% Rh/Al2O3, MeOH, 4.3 atm; (b) IBX, DMSO; (c) DMAP, Ac2O, Py; (d) 3 N HCl, H2O, dioxane, pH
1; (e) IBX, THF, reflux; (f) LiAlH(OtBut)3, THF, from -78 °C to room temperature; (g) TBDMSCl, imidazole, DMF; (h) 10% K2CO3,
MeOH.
Ta ble 2. Inotropic Activity on Electrically Driven Guinea Pig
Left Atrium
a
b
Emax
,
% increase
concn to obtain
EC50,
compd
from basal force
E
max, µM
µM
28
39
40
70
50
90
100
100
100
3
12
20
15
nd
116
39
117
118
digitoxigenin
digoxin
191
155
200
184
0.3
0.3
3
0.057
0.05
0.57
0.38
1
a
b
Maximal increase in force of contraction. Concentrations
producing 50% of the maximal increase in force of contraction were
calculated from concentration-response curves; nd: not deter-
mined.
Homologous oximes 35 and 36 showed a slight
decrease in affinity; further elongation, as in 37 and 38,
gave a further small decrease. Again, for the most active
of these simple oximes the distance between the skel-
eton and the amine seems to be 7 bonds.
F igu r e 2. Conformations of uzarigenin and epimeric 5â-(4-
hydroxycyclohexyl)perhydroindene derivatives.
Reduction of the oxime function to the hydroxyl-
amines 13 and 14 yielded a 3/5-fold decrease of affinity.
As far as the basic center is concerned, primary
amines showed slightly higher affinities in comparison
with the tertiary amines. A very high decrease in
affinity could be revealed for guanylhydrazones 12, 34,
43, and 44, since they showed 16/80-fold lower affinities
than the corresponding oximes.
In general in this perhydroindene series we have
found the same structure-activity relationships for the
substituent in position 1â seen for the substituents in
17â in the digitalis skeleton16 but with much more
marked differences among the same groups in the latter
case.
skeleton that any variation in the 17â-substituent
requires a rearrangment of the oxime chain in order to
allow the ionic coupling between the amonium group
and the anionic counterpart in the receptor to take
place. This may result in more pronounced differences
among the corresponding apparent binding energies. In
the case of perhydroindene derivatives, the opposite
behavior may occur. The best fitting energy could be the
result of a compromise between an optimized ionic
interaction of the oxime chain and the less stringent
hydrophobic bond of the more flexible 5-substituted
perhydroindene skeleton, which has more adaptive
characteristics. As a result, energy differences in this
series are minimized.
A tentative explanation may be that the strong
hydrophobic interaction with the receptor is so tight for
the rigid and peculiarly shaped 5â,14â-androstane
In otr op ic Activity. Compounds 28, 39, and 40 were
tested up to their maximum solubility. All showed low
positive inotropic effects when compared to the stand-

1-(O-Aminoalkyloximes) of Perhydroindene Derivatives
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 1 197
water and 1 N NaOH added until pH 9.5 was reached. The
mixture was extracted three times with EtOAc. The combined
organic layers were dried over Na2SO4 and evaporated in
vacuo. The residue was purified by flash chromatography and,
finally, transformed into the salt by adding the stoichiometric
amount of the corresponding acid.
P r ep a r a tion of Oxim es. Meth od B. To a solution of the
appropriate hydroxylamine (1.2 equiv) in 1 N NaOH/dioxane
5:2 (1.7 M) was added dropwise a solution of the appropriate
aldehyde (1 equiv) in dioxane (0.5 M) at room temperature.
After 3 h for compounds 39 and 40 or 2 days for compounds
41 and 42, the solution was diluted with water and extracted
three times with CHCl3. The combined organic layers were
dried over Na2SO4 and evaporated in vacuo. The residue was
purified by flash chromatography and, finally, transformed
into the salt by adding the stoichiometric amount of the
corresponding acid.
P r ep a r a tion of Hyd r oxyla m in es. Meth od C. A solution
of crude oxime as a base (1 equiv) in MeOH (0.2 M) was
adjusted to pH 3.0 with 1 N HCl under stirring at room
temperature. NaBH3CN (1.5 equiv) was added, followed by
water (0.1 mL/equiv). The reaction was continuously kept at
pH 3 by a pH-stat controlling the addition of 1 N HCl. After 6
h, NaBH3CN (0.75 equiv) was added followed by water (0.1
mL/equiv). Additions of NaBH3CN (0.4 equiv) and water (0.1
mL/equiv) were repeated after 24 and 30 h. After 48 h the
solution was brought to pH 1.8 with 1 N HCl. After being
stirred for 1 h, the solution was brought to pH 9.5 with 4 N
NaOH, and methanol was evaporated in vacuo. The mixture
was diluted with water and extracted three times with EtOAc.
The combined organic layers were dried over Na2SO4 and
evaporated in vacuo. The residue was purified by flash
chromatography and, finally, transformed into the salt by
adding the stoichiometric amount of the corresponding acid.
P r ep a r a tion of Gu a n ylh yd r a zon es. Meth od D. A sus-
pension of aminoguanidine hydrogencarbonate (1.2 equiv) in
dioxane/water 3:2 was brought to pH 4.5 for compounds 12
and 34 and to pH 3 for 43 and 44 with 1 N HCl. A solution of
appropriate aldehyde (1 equiv) in dioxane/water 2:1 was added
dropwise at room temperature. After 16 h for compounds 12
and 34 or 6 days for compounds 43 and 44, the mixture was
evaporated to dryness and the crude product purified by flash
chromatography.
ards, when considering the concentration producing
their maximum effects, suggesting that a higher binding
affinity might be requested to produce inotropic activity
on the isolated atria. However, the different distribution
and biochemical characteristics of the Na+,K+-ATPase
isoforms in different tissues and species should be
considered. In fact, the binding affinity was measured
on isolated and purified Na+,K+-ATPase from dog
kidney, which contains the R1 isoform, whereas the
inotropic activity was measured on the whole guinea pig
atria, which contains both R1, R2, and R3 isoforms.
Besides, it must be reminded that the sensitivity of the
Na+,K+-ATPase for cardiac glycosides is isoform- and
species-dependent (the affinity of the glycosides is
higher for the R3 than for the R1 and R2 isoforms, and
the canine Na+,K+-ATPase is more sensitive than the
rat and the guinea pig enzymes). Therefore it cannot
be excluded that this series of compounds may differ-
ently interact with the Na+,K+-ATPase isoforms (R1 and
R3).
Con clu sion s
Some perhydroindenic 1â-aminoalkyloximes pre-
sented in this paper showed good binding affinity to
Na+,K+-ATPase. The most active compounds revealed
IC50 values in the micromolar range. These compounds
were substituted in position 5â with a cyclohexyl group
and in position 1â with the same aminoalkyloxime
groups already reported with a digitoxigenin-like skel-
eton.16 The 5â-cyclohexylperhydroindene derivatives
showed a conformation best fitting to that of uzarigenin
but the binding affinities of the most active compounds
were 4/8-fold lower. This could mean that a strong
interaction of the basic amine with the anionic site of
the receptor is not sufficient to overcome the reduction
in affinity of the perhydroindene skeleton vs a steroidal
one, capable of binding to the receptor through van der
Waals interactions.
P r ep a r a tion of Oxim es. Meth od E. A solution of the
appropriate aldehyde in dioxane/water 3:2 was adjusted to pH
1 with 3 N HCl. After 2 h for compounds 84, 85, 110, and 115
or 16 h for compounds 96 and 97, a solution of NaOAc (4 equiv)
and the appropriate hydroxylamine (1.5 equiv) in dioxane/
water 3:2, previously adjusted to pH 4.5 with 6 N HCl, was
added dropwise. After 0.5 h dioxane was evaporated in vacuo.
The residue was diluted with water and 1 N NaOH added until
pH 9.5 was reached. The mixture was extracted three times
with EtOAc. The combined organic layers were dried over
Na2SO4 and evaporated in vacuo. The residue was purified by
flash chromatography and, finally, transformed into the salt
by adding the stoichiometric amount of the corresponding acid.
Such a reduction in binding affinities could be the
reason some compounds, chosen among those with the
highest affinities within this series, showed low positive
inotropic effects in the guinea pig left atrium.
Exp er im en ta l Section
Ch em istr y. Elemental analyses were performed by Redox,
1
Cologno Monzese, Italy. H NMR spectra were recorded on a
Bruker AC-300 spectrometer at 300.13 MHz (1H NMR) or at
75.48 MHz (13C NMR). Chemical shifts (δ) are given in ppm
downfield from tetramethylsilane as internal standard and
coupling constants (J values) are in hertz. NMR assignments
were drawn from classical arguments on chemical shift and
coupling constant behavior. Mass spectral data were obtained
with electron impact ionization technique at 70 eV from a
Finnigan INCOS-50 mass spectrometer using the direct
exposure probe (DEP). Chromatographies were carried out on
silica gel (Baker 7024-02) in all instances. Solvents and
reagents were used as purchased from suppliers.
(1S,3a S,7a R)-1-[3-Am in op r op oxy-(E)-im in om eth yl]-7a -
m eth ylp er h yd r oin d en -3a -ol Oxa la te (2). Prepared follow-
ing method A starting from 56. The crude product was purified
by chromatography in CHCl3/MeOH/26% w/v aqueous NH3 (9:
1:0.1) followed by salt formation with the stoichiometric
amount of oxalic acid in EtOH. After evaporation in vacuo of
the resulting solution, the residue was triturated with EtOAc
1
to give a white solid (0.26 g, 47%), mp 128-155 °C. H NMR
(DMSO-d6) δ 0.78 (s, 2.55H, CH3 (E) isomer), 0.84 (s, 0.45H,
CH3 (Z) isomer), 2.48 (m, 1H, CHCHdN), 2.87 (t, 2H, CH2N),
3.94 (t, 2H, CH2O), 6.71 (d, 0.15H, J ) 7.9, CHdN (Z) isomer),
7.40 (d, 0.85H, J ) 8.5, CHdN (E) isomer). MS m/z 237 (2),
164 (100).
(1S ,3a S ,7a R )-1-[2-Dim e t h yla m in oe t h oxy-(E )-im in o-
m eth yl]-5-[(E)-ben zyliden ]-7a-m eth ylper h ydr oin den -3a-ol
(3). Prepared following method A starting from 59. The crude
product on chromatography with CHCl3/MeOH/26% w/v aque-
ous NH3 (9:1:0.1) followed by trituration with i-Pr2O gave a
Intermediate hydroxylamines were prepared as previously
described.16
P r ep a r a tion of Oxim es. Meth od A. A solution of NaOAc
(4 equiv) and the appropriate hydroxylamine (1.05 equiv) in
dioxane/water 3:2 (0.1 M) was adjusted to pH 4.5 with 3 N
HCl. A solution of the appropriate aldehyde (1 equiv) in
dioxane/water 2:1 (0.2 M) was added dropwise at room
temperature. After 1 h for compounds 2-11, 15-33, 37, 38,
45, and 46, or 4 h for compound 35, or 16 h for compound 36,
dioxane was evaporated in vacuo. The residue was diluted with

198 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 1
Cerri et al.
1
white solid (0.26 g, 90%), mp 113-116 °C. H NMR (CDCl3) δ
(10). Prepared following method A starting from 73. The crude
product was purified by chromatography with CHCl3/MeOH/
26% w/v aqueous NH3 (9:5:0.5). The purified product (0.4 g)
was dissolved in EtOH, and the stoichiometric amount of oxalic
acid was added. After evaporation in vacuo, the residue was
triturated with Et2O to give 10 as a white solid (0.25 g, 44%),
mp 112-116 °C. 1H NMR (DMSO-d6) δ 0.90 (s, 3H, CH3), 2.30
(m, 1H, CHCHdN), 2.70 (m, 1H, W1/2h ) 25 Hz, CHPh), 2.70
(s, 6H, N(CH3)2), 3.21 (t, 2H, CH2N), 4.20 (t, 2H, CH2O), 7.20
(m, 5H, Ph), 7.57 (d, 1H, J ) 9.1, CHdN). 13C NMR (DMSO-
d6) δ 15.7 (q), 24.9 (t), 29.0 (t), 35.3 (t), 37.7 (t), 40.6 (t), 40.7
(d), 43.1 (q), 43.1 (q), 47.4 (s), 49.6 (d), 55.4 (t), 67.4 (t), 80.9
(s), 125.9 (d), 126.7 (d), 126.7 (d), 128.3 (d), 128.3 (d), 146.1
(s), 157.9 (d), 164.2 (s). MS m/z 344 (18, M+ base), 58 (100).
0.97 (s, 3H, CH3), 2.30 (s, 6H, N(CH3)2), 2.58 (t, 2H, CH2N),
2.74 (m, 1H, CHCHdN), 4.12 (t, 2H, CH2O), 6.30 (s, 1H,
CHPh), 7.19-7.35 (m, 5H, Ph), 7.54 (d, 1H, J ) 8.6, CHdN).
MS m/z 356 (7, M+), 58 (100).
(1S ,3a S ,7a R )-1-[2-Dim e t h yla m in oe t h oxy-(E )-im in o-
m eth yl]-5-[(Z)-ben zyliden -7a-m eth ylper h ydr oin den -3a-ol
(4). Prepared following method A starting from 60. The crude
product on chromatography with CHCl3/MeOH/26% w/v aque-
ous NH3 (95:5:0.5) followed by trituration with i-Pr2O gave a
white solid. (0.15 g, 47%), mp 110-112 °C. 1H NMR (CDCl3) δ
0.99 (s, 3H, CH3), 2.29 (s, 6H, N(CH3)2), 2.58 (t, 2H, CH2N),
2.70 (m, 1H, CHCHdN), 4.13 (t, 2H, CH2O), 6.41 (s, 1H,
CHPh), 7.19-7.34 (m, 5H, Ph), 7.55 (d, 1H, J ) 8.6, CHdN).
MS m/z 356 (9, M+), 58 (100).
(1S,3a S,5S,7a R)-1-[2-Dim eth yla m in oeth oxy-(E)-im in o-
m eth yl]-5-ben zyl-7a -m eth ylp er h yd r oin d en -3a -ol oxa la te
(5). Prepared following method A starting from 64. The crude
product was purified by chromatography with CHCl3/MeOH/
26% w/v aqueous NH3 (95:5:0.5) followed by salt formation
with the stoichiometric amount of oxalic acid in EtOAc. After
evaporation in vacuo of the resulting solution, the residue was
triturated with EtOAc to give 5 as white solid (0.23 g, 45%),
mp 152-178 °C.1H NMR (CD3OD) δ 0.81 (s, 3H, CH3), 2.48
(d, 2H, CH2Ph), 2.97 (s, 6H, N(CH3)2), 3.44 (m, 2H, CH2N),
4.32 (m, 2H, CH2O), 7.10-7.30 (m, 5H, Ph), 7.43 (d, 1H, J )
7.5, CHdN). MS m/z 358 (6, M+ base), 58 (100).
(1S,3a S,5S,7a R)-1-[2-Am in oeth oxy-(E)-im in om eth yl]-5-
p h en yl-7a -m eth ylp er h yd r oin d en -3a -ol (11). Prepared fol-
lowing method A starting from 73. The crude product was
purified by chromatography with CHCl3/MeOH/26% w/v aque-
ous NH3 (9:1:0.1) followed by trituration with Et2O to give a
1
white solid, (0.11 g, 11%), mp 92-95 °C. H NMR (CD3OD) δ
1.01 (s, 3H, CH3), 2.42 (m, 1H, CHCHdN), 2.76 (m, 1H, CHPh),
2.85 (t, 2H, CH2N), 4.00 (t, 2H, CH2O), 7.12-7.32 (m, 5H, Ph),
7.62 (d, 1H, J ) 9.1, CHdN).
(1S,3a S,5S,7a R)-1-(E)-Gu a n id in oim in om eth yl-5-p h en -
yl-7a-m eth ylper h ydr oin den -3a-ol h ydr och lor ide (12). Pre-
pared following method D starting from 73. The crude product
was purified by chromatography with CHCl3/MeOH/26% w/v
aqueous NH3 (8:2:0.3) followed by trituration with EtOAc to
give a white solid, (0.09 g, 25%), mp 231-232 °C. 1H NMR
(DMSO-d6) δ 0.91 (s, 3H, CH3), 2.55 (dt, 1H, CHCHdN), 2.70
(m, 1H, CHPh), 4.48 (s, OH), 7.14-7.30 (m, 5H, Ph), 7.40 (bb,
4H, guanidine), 7.61 (d, 1H, J ) 8.4, CHdN), 11.5 (bb, 1H,
guanidine). MS m/z 314 (6, M+ base), 296 (100).
(1S,3a S,5S,7a R)-1-[2-Dim eth yla m in oeth oxy-(E)-im in o-
methyl]-5-cyclohexylmethyl-7a-methylperhydroinden-3a-ol
(6). Prepared following method A starting from 68. The crude
product on chromatography with CHCl3/MeOH/26% w/v aque-
ous NH3 (95:5:0.5) followed by trituration with n-hexane gave
1
a white solid (0.081 g, 31%), mp 79-85 °C. H NMR (CD3OD)
δ 0.83 (s, 3H, CH3), 2.26 (s, 6H, N(CH3)2), 2.58 (t, 2H, CH2N),
2.89 (m, 1H, CHCHdN), 4.12 (t, 2H, CH2O), 7.34 (d, 1H, J )
7.5, CHdN). MS m/z 364 (1, M+), 58 (100).
(1S ,3a S ,5S ,7a R )-1-(2-Dim e t h yla m in oe t h oxya m in o-
m eth yl)-5-p h en yl-7a -m eth ylp er h yd r oin d en -3a -ol oxa la te
(13). Prepared following method C starting from 10. The crude
product was purified by chromatography with CHCl3/MeOH/
26% w/v aqueous NH3 (9:1:0.1). The purified product (0.085
g) was dissolved in EtOAc, and the stoichiometric amount of
oxalic acid was added. After evaporation in vacuo, the residue
was crystallized from EtOAc/EtOH to give a white solid (0.039
g, 20%), mp 115-130 °C. 1H NMR (CD3OD) δ 1.08 (s, 3H, CH3),
2.72 (m, 1H, CHPh), 2.93 (s, 6H, N(CH3)2), 2.90-3.25 (m, 2H,
CH2NO), 3.38 (t, 2H, CH2N), 3.98 (t, 2H, CH2O), 7.13-7.30
(m, 5H, Ph).
(1S ,3a S ,5S ,7a R )-1-(2-Am in oe t h oxya m in om e t h yl)-5-
p h en yl-7a -m eth ylp er h yd r oin d en -3a -ol Oxa la te (14). Pre-
pared following method C starting from 11. The crude product
was purified by chromatography with CHCl3/MeOH/26% w/v
aqueous NH3 (95:5:0.5) followed by salt formation with the
stoichiometric amount of oxalic acid in EtOAc/EtOH. After
evaporation in vacuo of the resulting solution, the residue was
triturated with EtOAc to give a white solid (0.10 g, 13%), mp
from 148 °C dec. 1H NMR (DMSO-d6) δ 1.00 (s, 3H, CH3), 2.70
(m, 1H, CHPh), 3.12 (t, 2H, CH2N), 3.35 (d, 2H, CH2NO), 4.24
(t, 2H, CH2O), 7.10-7.30 (m, 5H, Ph), 8.0 (bb, 3H, NH3+). MS
m/z 240 (100).
(1S,3a S,5R,7a R)-1-[2-Dim et h yla m in oet h oxy-(E)-im i-
n om et h yl]-5-b en zyl-7a -m et h ylp er h yd r oin d en -3a -ol (7).
Prepared following method A starting from 63. The crude
product on chromatography with CHCl3/MeOH/26% w/v aque-
ous NH3 (95:5:0.5) followed by trituration with Et2O gave a
1
white solid (0.10 g, 42%), mp 122-128 °C. H NMR (DMSO-
d6) δ 0.76 (s, 3H, CH3), 2.00 (m, 2H, CH2Ph), 2.12 (s, 6H,
N(CH3)2), 2.25 (m, 1H, CHCHdN), 2.40 (t, 2H, CH2N), 3.92 (t,
2H, CH2O), 4.19 (s, OH), 7.12-7.27 (m, 5H, Ph), 7.40 (d, 1H,
J ) 9.4, CHdN). MS m/z 358 (20, M+), 58 (100).
(1S,3a S,5R,7a R)-1-[2-Dim et h yla m in oet h oxy-(E)-im i-
n om eth yl]-5-cycloh exylm eth yl-7a-m eth ylper h ydr oin den -
3a -ol (8). Prepared following method A starting from 66. The
crude product on chromatography with CHCl3/MeOH/26% w/v
aqueous NH3 (9:1:0.1) followed by trituration with i-Pr2O gave
a white solid (0.065 g, 28%), mp 100-106 °C. 1H NMR (CD3OD)
δ 0.87 (s, 3H, CH3), 2.29 (s, 6H, N(CH3)2), 2.42 (m, 1H,
CHCHdN), 2.61 (t, 2H, CH2N), 4.08 (t, 2H, CH2O), 7.54 (d,
1H, J ) 9.3, CHdN). MS m/z 364 (7, M+), 58 (100).
(1S,3a S,5R,7a R)-1-[2-Dim et h yla m in oet h oxy-(E)-im i-
n om eth yl]-5-p h en yl-7a -m eth ylp er h yd r oin d en -3a -ol ox-
a la te (9). Prepared following method A starting from 71. The
crude product was purified by chromatography with CHCl3/
MeOH/26% w/v aqueous NH3 (97:3:0.3). The purified product
(0.40 g) was dissolved in EtOAc, and the stoichiometric amount
of oxalic acid was added. After evaporation in vacuo, the
residue was triturated with EtOH/Et2O to give 9 (0.13 g, 37%),
white solid, mp 132-135 °C. 1H NMR (DMSO-d6) δ 0.78 (s,
3H, CH3), 2.71 (s, 6H, N(CH3)2), 2.81 (m, 1H, W1/2h ) 25 Hz,
CHPh), 2.95 (m, 1H, CHCHdN), 3.21 (t, 2H, CH2N), 4.24 (t,
2H, CH2O), 7.20 (m, 5H, Ph), 7.43 (d, 1H, J ) 7.3, CHdN).
13C NMR (DMSO-d6) δ 18.5 (q), 21.5 (t), 28.5 (t), 30.8 (t), 36.7
(t), 38.4 (d), 40.2 (d), 43.0 (t), 43.1 (q), 43.1 (q), 45.2 (s), 55.4
(t), 67.6 (t), 78.3 (s), 125.7 (d), 126.7 (d), 126.7 (d), 128.2 (d),
128.2 (d), 146.9 (s), 154.4 (d), 164.2 (s), 164.2 (s). MS m/z 344
(7, M+ base), 58 (100).
(1S,3a S,5S,7a R)-1-[2-Dim eth yla m in oeth oxy-(E)-im in o-
methyl]-5-(3-methylphenyl)-7a-methylperhydroinden-3a-ol
(15). Prepared following method A starting from 82. The crude
product on chromatography with CHCl3/MeOH/26% w/v aque-
ous NH3 (95:5:0.5) followed by trituration with i-Pr2O gave a
1
white solid (0.17 g, 47%), mp 148-152 °C. H NMR (CD3OD)
δ 0.99 (s, 3H, CH3), 2.29 (s, 6H, N(CH3)2), 2.30 (s, 3H, CH3Ph),
2.40 (dt, 1H, CHCHdN), 2.62 (t, 2H, CH2N), 2.70 (m, 1H,
CHPh), 4.10 (t, 2H, CH2O), 6.96-7.17 (m, 4H, Ph), 7.57 (d,
1H, J ) 9.3, CHdN). MS m/z 358 (6, M+), 58 (100).
(1S,3a S,5S,7a R)-1-[2-Am in oeth oxy-(E)-im in om eth yl]-5-
(3-m eth ylp h en yl)-7a -m eth ylp er h yd r oin d en -3a -ol oxa la te
(16). Prepared following method A starting from 82. The crude
product was purified by chromatography with CHCl3/MeOH/
26% w/v aqueous NH3 (97:3:0.3) followed by salt formation
with the stoichiometric amount of oxalic acid in Et2O. The
suspension was filtered to give a white solid (0.17 g, 45%), mp
(1S,3a S,5S,7a R)-1-[2-Dim eth yla m in oeth oxy-(E)-im in o-
m eth yl]-5-p h en yl-7a -m eth ylp er h yd r oin d en -3a -ol oxa la te

1-(O-Aminoalkyloximes) of Perhydroindene Derivatives
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 1 199
1
143-148 °C dec. H NMR (CD3OD) δ 1.00 (s, 3H, CH3), 2.30
in d en -3a -ol (23). Prepared following method E starting from
85. The crude product on chromatography with CHCl3/MeOH/
26% w/v aqueous NH3 (95:5:0.5) followed by crystallization
from EtOAc/EtOH gave a white solid (0.20 g, 38%), mp 179-
181 °C. 1H NMR (CDCl3) δ 1.03 (s, 3H, CH3), 2.28 (s, 6H,
N(CH3)2), 2.52 (dt, 1H, CHCHdN), 2.58 (t, 2H, CH2N), 2.73
(m, 1H, CHPh), 4.12 (t, 2H, CH2O), 4.67 (s, 2H, CH2OH), 7.21-
7.33 (m, 4H, Ph), 7.64 (d, 1H, J ) 9.1, CHdN). MS m/z 374 (3,
M+), 58 (100).
(s, 3H, CH3Ph), 2.40 (m, 1H, CHCHdN), 2.70 (m, 1H, CHPh),
3.20 (t, 2H, CH2N), 4.20 (t, 2H, CH2O), 6.95-7.20 (m, 4H, Ph),
7.67 (d, 1H, J ) 9.3, CHdN). MS m/z 330 (6, M+ base), 270
(100).
(1S,3a S,5S,7a R)-1-[2-Dim eth yla m in oeth oxy-(E)-im in o-
methyl]-5-(4-methylphenyl)-7a-methylperhydroinden-3a-ol
(17). Prepared following method A starting from 83. The crude
product on chromatography with CHCl3/MeOH/26% w/v aque-
ous NH3 (95:5:0.5) followed by trituration with Et2O gave a
(1S,3a S,5S,7a R)-1-[2-Am in oeth oxy-(E)-im in om eth yl]-5-
(4-h yd r oxym eth ylp h en yl)-7a -m eth ylp er h yd r oin d en -3a -
ol (24). Prepared following method E starting from 85. The
crude product on chromatography with CHCl3/MeOH/26% w/v
aqueous NH3 (9:1:0.1) followed by trituration with Et2O/EtOAc
gave a white solid (0.20 g, 41%), mp 131-134 °C. 1H NMR
(CDCl3) δ 1.02 (s, 3H, CH3), 2.50 (dt, 1H, CHCHdN), 2.74 (m,
1H, CHPh), 2.93 (t, 2H, CH2N), 4.04 (t, 2H, CH2O), 4.67 (s,
2H, CH2OH), 7.20-7.32 (m, 4H, Ph), 7.63 (d, 1H, J ) 9.1,
CHdN). MS m/z 346 (9, M+), 286 (100).
1
white solid (0.24 g, 49%), mp 161-166 °C. H NMR (CDCl3) δ
1.04 (s, 3H, CH3), 2.29 (s, 6H, N(CH3)2), 2.33 (s, 3H, CH3Ph),
2.50 (dt, 1H, CHCHdN), 2.59 (t, 2H, CH2N), 2.71 (m, 1H,
CHPh), 4.13 (t, 2H, CH2O), 7.13 (m, 4H, Ph), 7.66 (d, 1H, J )
9.1, CHdN). MS m/z 358 (4, M+), 58 (100).
(1S,3a S,5S,7a R)-1-[2-Am in oeth oxy-(E)-im in om eth yl]-5-
(4-m eth ylp h en yl)-7a -m eth ylp er h yd r oin d en -3a -ol oxa la te
(18). Prepared following method A starting from 83. The crude
product was purified by chromatography with CHCl3/MeOH/
26% w/v aqueous NH3 (95:5:0.5) followed by salt formation
with the stoichiometric amount of oxalic acid in EtOAc.
Evaporation in vacuo of the resulting solution gave a white
(1S,3a S,5S,7a R)-1-[2-Dim eth yla m in oeth oxy-(E)-im in o-
m eth yl]-5-[4-(2-dim eth ylam in oeth oxy)ph en yl]-7a-m eth yl-
p er h yd r oin d en -3a -ol (25). Prepared following method A
starting from 100. The crude product on chromatography with
CHCl3/MeOH/26% w/v aqueous NH3 (9:1:0.1) followed by
trituration with i-Pr2O/EtOAc gave a white solid (0.08 g, 46%),
mp 126-128 °C. 1H NMR (CDCl3) δ 1.03 (s, 3H, CH3), 2.29 (s,
6H, N(CH3)2), 2.33 (s, 6H, N(CH3)2), 2.50 (dt, 1H, CHCHdN),
2.59 (t, 2H, CH2N), 2.72 (t, 2H, CH2N), 4.05 (t, 2H, CH2O),
4.12 (t, 2H, CH2O), 6.87 (d, 2H, Ph), 7.14 (d, 2H, Ph), 7.64 (s,
1H, J ) 9.1, CHdN). MS m/z 431 (17, M+), 58 (100).
1
solid (0.25 g, 41%), mp 158-161 °C. H NMR (CD3OD) δ 1.00
(s, 3H, CH3), 2.28 (s, 3H, CH3Ph), 2.45 (dt, 1H, CHCHdN),
2.69 (m, 1H, CHPh), 3.20 (m, 2H, CH2N), 4.17 (t, 2H, CH2O),
7.11 (m, 4H, Ph), 7.66 (d, 1H, J ) 9.3, CHdN). MS m/z 330 (2,
M+ base), 270 (100).
(1S,3a S,5S,7a R)-1-[2-Dim eth yla m in oeth oxy-(E)-im in o-
methyl]-5-(3-hydroxyphenyl)-7a-methylperhydroinden-3a-ol
(19). Prepared following method E starting from 96. The crude
product on chromatography with CHCl3/MeOH/26% w/v aque-
ous NH3 (95:5:0.5) followed by trituration with Et2O gave a
(1S,3a S,5S,7a R)-1-[2-Dim eth yla m in oeth oxy-(E)-im in o-
m eth yl]-5-(3-pyr idyl)-7a-m eth ylper h ydr oin den -3a-ol (26).
Prepared following method A starting from 94. The crude
product on chromatography with CHCl3/MeOH/26% w/v aque-
ous NH3 (97:3:0.3) followed by trituration with Et2O gave a
1
white solid (0.26 g, 36%), mp 142-146 °C. H NMR (CDCl3) δ
0.95 (s, 3H, CH3), 2.32 (s, 6H, N(CH3)2), 2.45 (dt, 1H,
CHCHdN), 2.65 (t, 2H, CH2N), 2.67 (m, 1H, CHPh), 4.15 (t,
2H, CH2O), 6.65-6.72 (m, 3H, Ph), 7.13 (t, 1H, Ph), 7.57 (d,
1H, J ) 9.1, CHdN). MS m/z 360 (6, M+), 58 (100).
1
white solid (0.09 g, 38%), mp 114-124 °C. H NMR (CDCl3) δ
1.07 (s, 3H, CH3), 2.31 (s, 6H, N(CH3)2), 2.54 (dt, 1H,
CHCHdN), 2.60 (t, 2H, CH2N), 2.77 (m, 1H, CHPy), 4.15 (t,
2H, CH2O), 7.25 (m, 1H, Py), 7.56 (m,1H, Py), 7.68 (s, 1H, J )
9.1, CHdN), 8.48 (m, 2H, Py). MS m/z 345 (9, M+), 58 (100).
(1S,3a S,5S,7a R)-1-[2-Dim eth yla m in oeth oxy-(E)-im in o-
methyl]-5-(4-hydroxyphenyl)-7a-methylperhydroinden-3a-ol
(20). Prepared following method E starting from 97. The crude
product on chromatography with CHCl3/MeOH/26% w/v aque-
ous NH3 (9:1:0.1) followed by trituration with Et2O gave a
(1S,3a S,5S,7a R)-1-[2-Dim eth yla m in oeth oxy-(E)-im in o-
m eth yl]-5-(4-pyr idyl)-7a-m eth ylper h ydr oin den -3a-ol (27).
Prepared following method A starting from 95. The crude
product was purified by chromatography with CHCl3/MeOH/
26% w/v aqueous NH3 (95:5:0.5) and triturated with i-Pr2O.
The residue was dissolved with EtOAc and filtered through a
basic aluminum oxide pad, followed by trituration with n-
hexane to give a white solid (0.007 g, 20%), mp 131-136 °C.
1H NMR (CDCl3) δ 1.04 (s, 3H, CH3), 2.31 (s, 6H, N(CH3)2),
2.54 (dt, 1H, CHCHdN), 2.61 (t, 2H, CH2N), 2.69 (m, 1H,
CHPy), 4.14 (t, 2H, CH2O), 7.15 (m, 2H, Py), 7.64 (s, 1H, J )
9.1, CHdN), 8.52 (m, 2H, Py). MS m/z 345 (1, M+), 58 (100).
1
white solid (0.099 g, 16%), mp 211-214 °C. H NMR (DMSO-
d6) δ 0.85 (s, 3H, CH3), 2.12 (s, 6H, N(CH3)2), 2.28 (m, 1H,
CHCHdN), 2.43 (t, 2H, CH2N), 2.55 (m, 1H, CHPh), 3.95 (t,
2H, CH2O), 4.30 (s, 1H, OH), 6.65 (d, 2H, Ph), 7.01 (d, 2H,
Ph), 7.47 (d, 1H, J ) 9.3, CHdN), 9.13 (s, 1H, PhOH). MS m/z
360 (2, M+), 58 (100).
(1S,3a S,5S,7a R)-1-[2-Dim eth yla m in oeth oxy-(E)-im in o-
m eth yl]-5-(3-h yd r oxym eth ylp h en yl)-7a -m eth ylp er h yd r o-
in d en -3a -ol (21). Prepared following method E starting from
84. The crude product on chromatography with CHCl3/MeOH/
26% w/v aqueous NH3 (9:1:0.1) followed by trituration with
Et2O gave a white solid (0.12 g, 48%), mp 160-164 °C. 1H NMR
(DMSO-d6) δ 0.88 (s, 3H, CH3), 2.16 (s, 6H, N(CH3)2), 2.30 (dt,
1H, CHCHdN), 2.45 (t, 2H, CH2N), 2.69 (m, 1H, CHPh), 3.95
(t, 2H, CH2O), 4.35 (s, 1H, OH), 4.45 (d, 2H, CH2OH), 5.12 (t,
HOCH2), 7.06-7.28 (m, 4H, Ph), 7.48 (d, 1H, J ) 9.4, CHdN).
MS m/z 374 (5, M+), 58 (100).
(1S,3a S,5S,7a R)-1-[2-Dim eth yla m in oeth oxy-(E)-im in o-
m eth yl]-5-cycloh exyl-7a-m eth ylper h ydr oin den -3a-ol (28).
Prepared following method A starting from 75. The crude
product on chromatography with CHCl3/MeOH/26% w/v aque-
ous NH3 (9:1:0.1) followed by trituration with Et2O gave a
1
white solid (0.10 g, 15%), mp 109-120 °C. H NMR (CD3OD)
δ 0.87 (s, 3H, CH3), 2.28 (s, 6H, N(CH3)2), 2.35 (dt, 1H,
CHCHdN), 2.61 (t, 2H, CH2N), 4.08 (t, 2H, CH2O), 7.54 (d,
1H, J ) 9.1, CHdN). MS m/z 350 (4, M+), 58 (100).
(1S,3a S,5S,7a R)-1-[2-Am in oeth oxy-(E)-im in om eth yl]-5-
(3-h yd r oxym eth ylp h en yl)-7a -m eth ylp er h yd r oin d en -3a -
ol oxa la te (22). Prepared following method E starting from
84. The crude product was purified by chromatography with
CHCl3/MeOH/26% w/v aqueous NH3 (9:1:0.1) followed by salt
formation with the stoichiometric amount of oxalic acid in
EtOH. After evaporation in vacuo of the resulting solution,
the residue was triturated with i-Pr2O to give a white solid
(0.04 g, 16%), mp 140-142 °C. 1H NMR (CD3OD) δ 1.02 (s,
3H, CH3), 2.45 (m, 1H, CHCHdN), 3.21 (t, 2H, CH2N), 4.17
(t, 2H, CH2O), 4.58 (s, 2H, CH2OH), 7.13-7.28 (m, 4H, Ph),
7.67 (d, 1H, J ) 9.3, CHdN). MS m/z 346 (5, M+ base), 286
(100).
(1S,3a S,5S,7a R)-1-[3-Dim eth yla m in op r op oxy-(E)-im i-
n om eth yl]-5-cycloh exyl-7a -m eth ylp er h yd r oin d en -3a -ol
Oxa la te (29). Prepared following method A starting from 75.
The crude product was purified by chromatography with
CHCl3/MeOH/26% w/v aqueous NH3 (95:5:0.5) followed by
trituration with i-Pr2O. The purified product as a base was
dissolved in EtOAc, and the stoichiometric amount of oxalic
acid was added. The suspension was filtered to give a white
1
solid (0.26 g, 44%), mp 140-149 °C. H NMR (CD3OD) δ 0.87
(s, 3H, CH3), 2.35 (dt, 1H, CHCHdN), 2.87 (s, 6H, N(CH3)2),
3.20 (m, 2H, CH2N), 4.05 (t, 2H, CH2O), 7.55 (d, 1H, J ) 9.1,
CHdN). MS m/z 365 (2, M+1 base), 246 (100).
(1S,3a S,5S,7a R)-1-[2-Dim eth yla m in oeth oxy-(E)-im in o-
m eth yl]-5-(4-h yd r oxym eth ylp h en yl)-7a -m eth ylp er h yd r o-

200 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 1
Cerri et al.
(1S,3a S,5S,7a R)-1-[4-Dim et h yla m in ob u t oxy-(E)-im i-
n om eth yl]-5-cycloh exyl-7a -m eth ylp er h yd r oin d en -3a -ol
(30). Prepared following method A starting from 75. The crude
product on chromatography with CHCl3/MeOH/26% w/v aque-
ous NH3 (95:5:0.5) gave a white solid (0.35 g, 69%), mp 58-63
°C. 1H NMR (CD3OD) δ 0.90 (s, 3H, CH3), 2.22 (s, 6H, N(CH3)2),
2.28 (m, 2H, CH2N), 2.43 (dt, 1H, CHCHdN), 4.00 (t, 2H,
CH2O), 7.56 (d, 1H, J ) 9.1, CHdN). MS m/z 379 (1, M+1),
116 (100).
(1S,3a S,5S,7a R)-1-[2-Dim eth yla m in oeth oxy-(E,Z)-im i-
n op r op yl]-5-cycloh exyl-7a -m et h ylp er h yd r oin d en -3a -ol
Oxa la te (37). Prepared following method A starting from 106.
The crude product was purified by chromatography with
CHCl3/MeOH/26% w/v aqueous NH3 (95:5:0.5) followed by salt
formation with the stoichiometric amount of oxalic acid in
EtOAc. After evaporation in vacuo of the resulting solution,
the residue was triturated with i-Pr2O to give a white solid
(0.10 g, 20%), mp 137-139 °C. 1H NMR (CD3OD) δ 0.92 (s,
3H, CH3), 2.92 (s, 6H, N(CH3)2), 3.43 (m, 2H, CH2N), 4.28 (m,
1.6H, CH2O (E) isomer), 4.37 (m, 0.4H, CH2O (Z) isomer), 6.80
(t, 0.2H, CHdN (Z) isomer), 7.50 (t, 0.8H, CHdN (E) isomer).
MS m/z 378 (5, M+ base), 58 (100).
(1S,3a S,5S,7a R)-1-[2-Am in oeth oxy-(E,Z)-im in op r op yl]-
5-cycloh exyl-7a -m et h ylp er h yd r oin d en -3a -ol H em iox-
a la te (38). Prepared following method A starting from 106.
The crude product was purified by chromatography with
CHCl3/MeOH/26% w/v aqueous NH3 (9:1:0.1) followed by salt
formation with the stoichiometric amount of oxalic acid in
EtOAc. After evaporation in vacuo of the resulting solution,
the residue was triturated with i-Pr2O to give a white solid
(0.11 g, 25%), mp 161-163 °C. 1H NMR (CD3OD) δ 0.92 (s,
3H, CH3), 3.20 (m, 2H, CH2N), 4.18 (t, 1.6H, CH2O (E) isomer),
4.24 (t, 0.4H, CH2O (Z) isomer), 6.77 (t, 0.2H, CHdN (Z)
isomer), 7.50 (t, 0.8H, CHdN (E) isomer). MS m/z 350 (2, M+
base), 55 (100).
(1R,3a S,5S,7a R)-1-[(E,E)-3-(2-Dim et h yla m in oet h oxy-
im in o)-1-p r op e n yl]-5-cycloh e xyl-7a -m e t h ylp e r h yd r o-
in d en -3a -ol Oxa la te (39). Prepared following method B
starting from 105. The crude product on chromatography with
CHCl3/MeOH/26% w/v aqueous NH3 (95:5:0.5) followed by salt
formation with the stoichiometric amount of oxalic acid in
EtOAc gave a white solid (0.15 g, 27%), mp 137-144 °C. 1H
NMR (DMSO-d6) δ 0.72 (s, 3H, CH3), 2.24 (m, 1H, CHCHd),
2.68 (s, 6H, N(CH3)2), 3.20 (t, 2H, CH2N), 4.23 (t, 2H, CH2O),
5.85 (dd, 0.9H, J ) 9.9, 15.4, CH-CHdN (E) isomer), 6.33 (dd,
0.9H, J ) 10.4, 15.4, CHdCH-CHdN (E) isomer), 6.40 (m,
0.2H, CHdCH-CHdN (Z) isomer), 7.20 (d, 0.1H, J ) 8.9,
CHdN (Z) isomer), 7.81 (d, 0.9H, J ) 9.9, CHdN (E) isomer).
MS m/z 376 (40, M+ base), 95 (100).
(1S,3a S,5S,7a R)-1-[2-Am in oeth oxy-(E)-im in om eth yl]-5-
cycloh exyl-7a -m eth ylp er h yd r oin d en -3a -ol Oxa la te (31).
Prepared following method A starting from 75. The crude
product was purified by chromatography with CHCl3/MeOH/
26% w/v aqueous NH3 (9:1:0.1) followed by salt formation with
the stoichiometric amount of oxalic acid in EtOAc. Evaporation
in vacuo of the resulting solution gave a white solid (0.10 g,
32%), mp 162-165 °C. 1H NMR (DMSO-d6) δ 0.76 (s, 3H, CH3),
2.25 (dt, 1H, CHCHdN), 2.94 (t, 2H, CH2N), 4.00 (t, 2H,
CH2O), 7.54 (d, 1H, J ) 9.1, CHdN). MS m/z 322 (2, M+ base),
262 (100).
(1S,3a S,5S,7a R)-1-[3-Am in op r op oxy-(E)-im in om eth yl]-
5-cycloh exyl-7a -m et h ylp er h yd r oin d en -3a -ol (32). Pre-
pared following method A starting from 75. The crude product
on chromatography with CHCl3/MeOH/26% w/v aqueous NH3
(95:5:0.5) followed by salt formation with the stoichiometric
amount of oxalic acid in EtOAc gave a white solid (0.20 g, 45%),
1
mp 71-93 °C. H NMR (CDCl3) δ 0.90 (s, 3H, CH3), 2.42 (dt,
1H, CHCHdN), 2.80 (t, 2H, CH2N), 4.08 (t, 2H, CH2O), 7.57
(d, 1H, J ) 9.1, CHdN). MS m/z 337 (2, M+1), 246 (100).
(1S,3a S,5S,7a R)-1-[4-Am in ob u t oxy-(E)-im in om et h yl]-
5-cycloh exyl-7a-m eth ylper h ydr oin den -3a-ol Oxalate (33).
Prepared following method A starting from 75. The crude
product on chromatography with CHCl3/MeOH/26% w/v aque-
ous NH3 (9:1:0.1) followed by salt formation with the stoichio-
metric amount of oxalic acid in EtOAc gave a white solid (0.23
g, 35%), mp 110-132 °C dec. 1H NMR (CDCl3) δ 0.86 (s, 2.7H,
CH3 (E) isomer), 0.95 (s, 0.3H, CH3 (Z) isomer), 2.34 (dt, 1H,
CHCHdN), 2.95 (t, 2H, CH2N), 4.00 (t, 2H, CH2O), 6.83 (d,
0.1H, J ) 8.4, CHdN (Z) isomer), 7.53 (d, 0.9H, J ) 9.6, CHdN
(E) isomer). MS m/z 350 (6, M+ base), 88 (100).
(1R,3a S,5S,7a R)-1-[(E,E)-3-(2-Am in oet h oxyim in o)-1-
p r op en yl]-5-cycloh exyl-7a -m et h ylp er h yd r oin d en -3a -ol
Oxa la te (40). Prepared following method B starting from 105.
The crude product on chromatography with CHCl3/MeOH/26%
w/v aqueous NH3 (95:5:0.5) followed by salt formation with
the stoichiometric amount of oxalic acid in EtOAc gave a white
solid (0.15 g, 28%), 136-140 °C dec. 1H NMR (DMSO-d6) δ
0.72 (s, 3H, CH3), 2.24 (m, 1H, CHCHd), 3.05 (m, 2H, CH2N),
4.12 (t, 2H, CH2O), 5.84 (dd, 1H, J ) 9.9, 15.4, CHdCH-
CHdN), 6.33 (dd, 1H, J ) 10.4, 15.4, CHdCH-CHdN), 7.80
(d, 1H, J ) 9.9, CHdN), 7.82 (br b, 3H, NH3+). MS m/z 348
(43, M+ base), 95 (100).
(1R,3a S,5S,7a R)-1-[(E,E)-2-Meth yl-3-(2-d im eth yla m in o-
eth oxyim in o)-1-p r op en yl]-5-cycloh exyl-7a -m eth ylp er h y-
d r oin d en -3a -ol Oxa la te (41). Prepared following method B
starting from 108. The crude product on chromatography with
CHCl3/MeOH/26% w/v aqueous NH3 (95:5:0.5) followed by salt
formation with the stoichiometric amount of oxalic acid in
EtOAc gave a white solid (0.21 g, 47%), mp 164-167 °C. 1H
NMR (CD3OD) δ 0.82 (s, 3H, CH3), 1.77 (s, 3H, dCCH3), 2.73
(m, 1H, CHCH)), 2.92 (s, 6H, N(CH3)2), 3.44 (m, 2H, CH2N),
4.35 (m, 2H, CH2O), 6.04 (d, 1H, CHdC), 7.77 (s, 1H, CHdN).
MS m/z 390 (21, M+ base), 71 (100).
(1R,3a S,5S,7a R)-1-[(E,E)-2-Met h yl-3-(2-a m in oet h oxy-
im in o)-1-p r op e n yl]-5-cycloh e xyl-7a -m e t h ylp e r h yd r o-
in d en -3a -ol Oxa la te (42). Prepared following method B
starting from 108. The crude product on chromatography with
CHCl3/MeOH/26% w/v aqueous NH3 (95:5:0.5) followed by salt
formation with the stoichiometric amount of oxalic acid in
EtOAc gave a white solid (0.31 g, 74%), mp 164-166 °C. 1H
NMR (CD3OD) δ 0.83 (s, 3H, CH3), 1.77 (s, 3H, dCCH3), 2.73
(m, 1H, CHCHd), 3.23 (t, 2H, CH2N), 4.24 (t, 2H, CH2O), 6.03
(d, 1H, CHdC), 7.78 (s, 1H, CHdN). MS m/z 362 (7, M+ base),
94 (100).
(1S,3a S,5S,7a R)-1-(E)-Gu a n id in oim in om eth yl-5-cyclo-
h exyl-7a -m eth ylp er h yd r oin d en -3a -ol (34). Prepared fol-
lowing method D starting from 75. The crude product on
chromatography in CHCl3/MeOH/26% w/v aqueous NH3 (80:
20:3) followed by trituration with EtOAc gave a white solid
1
(0.07 g, 29%), mp 150-160 °C. H NMR (DMSO-d6) δ 0.74 (s,
3H, CH3), 2.30 (m, 1H, CHCHdN), 4.04 (s, 1H, OH), 5.70 (bb,
4H, guanidine), 7.42 (d, 1H, J ) 8.4, CHdN). MS m/z 320 (18,
M+), 302 (100).
(1R,3a S,5S,7a R)-1-[2-Dim eth yla m in oeth oxy-(E,Z)-im i-
n oeth yl]-5-cycloh exyl-7a-m eth ylper h ydr oin den -3a-ol Ox-
a la te (35). Prepared following method A starting from 103.
The crude product on chromatography with CHCl3/MeOH/26%
w/v aqueous NH3 (95:5:0.5) followed by salt formation with
the stoichiometric amount of oxalic acid in EtOAc gave a white
1
solid (0.07 g, 10%), mp 105-121 °C. H NMR (CD3OD) δ 0.93
(s, 1.5H, CH3), 0.94 (s, 1.5H, CH3), 2.92 (s, 3H, N(CH3)2), 2.93
(s, 3H, N(CH3)2), 3.40-3.50 (m, 2H, CH2N), 4.30 (m, 1H,
CH2O), 4.36 (m, 1H, CH2O), 6.80 (0.5H, t, CHdN (Z) isomer),
7.45 (0.5H, dd, CHdN (E) isomer).
(1R,3a S,5S,7a R)-1-[2-Am in oeth oxy-(E,Z)-im in oeth yl]-
5-cycloh exyl-7a-m eth ylper h ydr oin den -3a-ol Oxalate (36).
Prepared following method A starting from 103. The crude
product was purified by chromatography with CHCl3/MeOH/
26% w/v aqueous NH3 (95:5:0.5) followed by salt formation
with the stoichiometric amount of oxalic acid in EtOAc. After
evaporation in vacuo of the resulting solution, the residue was
triturated with Et2O to give a white solid (0.03 g, 64%), mp
1
154-159 °C. H NMR (CD3OD) δ 0.95 (s, 3H, CH3), 3.20 (m,
2H, CH2N), 4.18 (m, 1.5H, CH2O (E) isomer), 4.23 (m, 0.5H,
CH2O (Z) isomer), 6.76 (0.25H, t, CHdN (Z) isomer), 7.45
(0.75H, dd, CHdN (E) isomer). MS m/z 336 (1, M+ base), 55
(100).

1-(O-Aminoalkyloximes) of Perhydroindene Derivatives
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 1 201
(1R,3aS,5S,7aR)-1-[(E,E)-3-Gu an idin oim in o-1-pr open yl]-
5-cycloh exyl-7a -m et h ylp er h yd r oin d en -3a -ol (43). Pre-
pared following method D starting from 105. The crude
product on chromatography with CHCl3/MeOH/26% w/v aque-
ous NH3 (85:15:1.5) followed by trituration with n-hexane gave
a white solid (0.13 g, 36%), mp 95-180 °C dec. 1H NMR
(DMSO-d6) δ 0.72 (s, 3H, CH3), 2.43 (m, 1H, CHCH)), 3.98
(s, 1H, OH), 5.60 (bb, 4H, guanidine), 5.75-6.10 (m, 2H,
HCdCH), 7.60 (d, 1H, CHdN). MS m/z 346 (0.1, M+), 111
(100).
(1R,3a S,5S,7a R)-1-[(E,E)-2-Met h yl-3-gu a n id in oim in o-
1-p r op en yl]-5-cycloh exyl-7a -m et h ylp er h yd r oin d en -3a -
ol Hyd r och lor id e (44). Prepared following method D starting
from 108. The crude product on chromatography with CHCl3/
MeOH/26% w/v aqueous NH3 (85:15:1.5) followed by tritura-
tion with Et2O gave a white solid (0.16 g, 44%), mp 226-265
°C. 1H NMR (CD3OD) δ 0.84 (s, 3H, CH3), 1.85 (d, 3H, J )
1.2, dCCH3), 2.78 (m, 1H, CHCHd), 6.15 (bd, 1H, J ) 10.6,
CHdC), 7.67 (s, 1H, CHdN). MS m/z 360 (present, M+ base),
125 (100).
at room temperature for 1 h, the solution was cooled to 0 °C,
and the following were added in order: water (7.0 mL, 0.39
mol), sodium perborate (74.5 g, 0.48 mol), and 4 N NaOH (0.12
L, 0.48 mol). The mixture was stirred at room temperature
for 16 h. The organic layer was separated, and the aqueous
one was extracted with EtOAc (3×). The combined organic
layers were washed with water, dried over Na2SO4, and
evaporated to dryness. The crude product was purified by flash
chromatography (n-hexane/acetone/CHCl3 4:3:3) to give the 1â
isomer 49 (41.14 g, 50%) and the 1R isomer 50 (16.45 g, 20%),
as white foams. Isomer 49: 1H NMR (CDCl3) δ 0.91 (s, 3H,
CH3), 3.56 (dd, 1H, CHHOH), 3.60 (br, 1H, OH), 3.64 (dd, 1H,
CHHOH), 3.98 (m, 4H, 2 OCH2). 13C NMR (CDCl3) δ 16.7 (q),
22.4 (t), 30.3 (t), 30.8 (t), 35.4 (t), 41.5 (t), 44.1 (d), 44.6 (s),
64.2 (t), 64.3 (t), 64.5 (t), 81.6 (s), 109.3 (s). Anal. (C13H22O4)
C, H. Isomer 50: 1H NMR (CDCl3) δ 1.11 (s, 3H, CH3), 3.59
(dd, 1H, CHHOH), 3.78 (dd, 1H, CHHOH), 3.95 (m, 4H, 2
OCH2). 13C NMR (CDCl3) δ 16.9 (q), 24.0 (t), 27.4 (t), 30.1 (t),
34.9 (t), 41.7 (t), 45.6 (s), 50.1 (d), 63.7 (t), 64.3 (t), 64.4 (t),
83.8 (s), 108.8 (s). Anal. (C13H22O4) C, H.
(1S,3a S,7a R)-1-Hyd r oxym eth yl-3a -h yd r oxy-7a -m eth yl-
5-p er h yd r oin d en on e (51). Compound 49 (41.14 g, 0.17 mol)
was dissolved in a 1 N solution of PTSA (0.411 L, 0.411 mol)
in CH3CN:H2O (85:15). After being stirred for 16 h, the mixture
was neutralized with solid NaHCO3, and CH3CN was evapo-
rated. The residue was extracted with EtOAc (3 ×), and the
combined organic layers were dried over Na2SO4 and evapo-
rated to dryness. The crude product was purified by flash
chromatography (n-hexane/CHCl3/acetone, 4:3:3) to give 51
(1S,3a S,5S,7a R)-1-[2-Dim eth yla m in oeth oxy-(E)-im in o-
m et h yl]-5-(4-cis-h yd r oxy-r -1-cycloh exyl)-7a -m et h ylp er -
h yd r oin d en -3a -ol (45). Prepared following method E starting
from 110. The crude product on chromatography with CHCl3/
MeOH/26% w/v aqueous NH3 (93:7:0.3) followed by trituration
with i-Pr2O gave a white solid (0.089 g, 51%), mp 98-121 °C.
1H NMR (CD3OD) δ 0.88 (s, 3H, CH3), 2.28 (s, 6H, N(CH3)2),
2.36 (dt, 1H, CHCHdN), 2.61 (t, 2H, CH2N), 3.90 (br s, 1H,
CHOH), 4.08 (t, 2H, CH2O), 7.54 (d, 1H, J ) 9.0, CHdN). MS
m/z 366 (10, M+), 58 (100).
1
(22.77 g, 68%) as a thick oil. H NMR (CDCl3) δ 1.21 (s, 3H,
CH3), 3.53 (dd, 1H, CHHOH), 3.79 (dd, 1H, CHHOH), 4.20 (br,
1H, OH), 5.10 (br, 1H, OH). 13C NMR (CDCl3) δ 14.5 (q), 22.0
(t), 37.0 (t), 37.2 (t), 37.2 (t), 46.5 (s), 48.5 (t), 49.3 (d), 62.2 (t),
82.9 (s), 209.9 (s).
(1R,3a S,7a R)-3a -Hyd r oxy-7a -m eth ylp er h yd r oin d en e-
5-sp ir o-2′-(1′,3′-d ioxola n e)-1-ca r boxa ld eh yd e (52). To a
solution of 50 (8.00 g, 0.033 mol) in THF (0.16 L) was added
IBX (13.86 g, 0.049 mol), and the resulting suspension was
heated to reflux for 1 h. After cooling to room temperature,
the precipitate was filtered off and the organic solvent
evaporated to dryness to give 52 (8.8 g, 100%) as a white foam.
1H NMR (CDCl3) δ 1.27 (s, 3H, CH3), 2.85 (dt, 1H, CHCHO),
3.90 (m, 4H, 2 CH2O), 9.80 (d, 1H, CHO).
(1S,3a S,7a R)-1-H yd r oxym et h yl-5-sp ir o-2′-(1′,3′d ioxo-
la n e)-7a -m eth ylp er h yd r oin d en -3a -ol (49). A solution of 52
(24.5 g, 0.102 mol) and 1.4 M methanolic KOH (0.612 L, 0.856
mol) was stirred at room temperature for 0.5 h. After cooling
to -20 °C, NaBH4 (4.05 g, 0.107 mol) was added, and mixture
was stirred for 2.5 h. After heating to room temperature, the
mixture was neutralized with CH3COOH and the organic
solvent evaporated. The crude product was purified by flash
chromatography (n-hexane/CHCl3/acetone, 4:3:3) to give 49
(15.88 g, 64%) and 50 (8.7 g, 35%) as white foams.
(1S,3a S,7a R)-1-Hyd r oxym eth yl-5-sp ir o-2′-(1′,3′-d ith io-
la n e)-7a -m eth ylp er h yd r oin d en -3a -ol (54). To a solution of
51 (2.24 g, 0.113 mol) and 1,2-ethanedithiol (1.35 mL, 0.018
mol) in CH2Cl2 (20 mL) at 0 °C was added BF3‚Et2O (0.36 mL,
2.8 mmol). The resulting mixture was stirred at room tem-
perature for 16 h. Then 1 N NaOH was added until neutral
pH. The layers were separated, and the aqueous phase was
extracted with CH2Cl2. The combined organic layers were dried
over Na2SO4 and evaporated to dryness. The crude product
was purified by flash chromatography (n-hexane/CHCl3/
acetone, 6:2:2) to give 54 (1.39 g, 45%) as an oil. 1H NMR
(CDCl3) δ 0.92 (s, 3H, CH3), 3.39 (m, 4H, 2 CH2S), 3.60 (dd,
1H, CHHOH), 3.68 (dd, 1H, CHHOH).13C (CDCl3) δ 16.8 (q),
22.3 (t), 33.7 (t), 36.5 (t), 36.9 (t), 38.2 (t), 38.3 (t), 44.1 (s),
44.6 (d), 48.5 (t), 64.4 (t), 66.4 (s), 81.6 (s).
(1S,3a S,5S,7a R)-1-[2-Dim eth yla m in oeth oxy-(E)-im in o-
m eth yl]-5-(4-tr a n s-h ydr oxy-r -1-cycloh exyl)-7a-m eth ylper -
h yd r oin d en -3a -ol (46). Prepared following method E starting
from 115. The crude product on chromatography with CHCl3/
MeOH/26% w/v aqueous NH3 (9:1:0.1) followed by trituration
with Et2O gave a white solid (0.094 g, 52%), mp 139-140 °C.
1H NMR (CD3OD) δ 0.87 (s, 3H, CH3), 2.28 (s, 6H, N(CH3)2),
2.61 (t, 2H, CH2N), 3.44 (m, 1H, W1/2 ) 21 Hz, CHOH), 4.08
(t, 2H, CH2O), 7.55 (d, 1H, J ) 9.0, CHdN).
(3a S,7a R)-1-Meth ylen -3a -h yd r oxy-7a -m eth ylp er h yd r o-
in d en e-5-sp ir o-2′-(1′,3′-d ioxola n e) (48). To a solution of 47
(100 g, 0.55 mol) and oxalic acid (30.0 g, 0.325 mol) in CH3CN
(1.5 L) was added ethylene glycol (1.1 L, 19.5 mol). After 16 h
the mixture was neutralized with 5% aqueous Na2CO3, and
CH3CN was evaporated. The residue was extracted with
chloroform (3×). The combined organic extracts were dried
over Na2SO4 and evaporated to dryness under reduced pres-
sure to afford (3aS,7aS)-3a-hydroxy-5-spiro-2′-(1′,3′-dioxolane)-
7a-methyl-1-perhydroindenone (105.0 g, 83%), as an oil. 1H
NMR (CDCl3) δ 1.01 (s, 3H, CH3), 2.20 (dt, 1H, H2), 2.53 (ddd,
1H, H2), 3.50 (s, 1H, OH), 3.96 (m, 4H, 2CH2O). 13C NMR
(DMSO-d6) (digitalis-like conformation) δ 13.3 (q), 28.3 (t), 29.3
(t), 30.9 (t), 33.2 (t), 42.3 (t), 52.1 (s), 64.0 (t), 64.2 (t), 78.2 (s),
108.0 (s), 220.6 (s). 13C NMR (CDCl3) (non-digitalis-like
conformation) δ 18.4 (q), 26.6 (t), 31.1 (t), 31.4 (t), 33.9 (t), 42.6
(t), 52.7 (s), 64.2 (t), 64.5 (t), 78.5 (s), 108.6 (s), 218.6 (s).
To a solution of (3aS,7aS)-3a-hydroxy-5-spiro-2′-(1′,3′-dioxo-
lane)-7a-methyl-1-perhydroindenone (100 g, 0.44 mol) and
methyltriphenylphosphonium bromide (1580 g, 4.42 mol) in
THF (1 L) were added potassium tert-butoxide (496 g, 4.42 mol)
and tert-BuOH (18 mL) dropwise at room temperature. The
mixture was heated to reflux for 2 h. After cooling to room
temperature, the mixture was neutralized with glacial acetic
acid. The precipitate was filtered off and washed with CH2Cl2,
and the filtrate was evaporated to dryness to give 48 (76.0 g,
1
77%) as an oil. H NMR (CDCl3) δ 1.00 (s, 3H, CH3), 3.45 (br,
1H, OH), 3.95 (m, 4H, 2CH2O), 4.80 (t, 1H, dCHH), 4.85 (t,
1H, dCHH).
(1S,3a S,7a R)-1-Hyd r oxym et h yl-5-sp ir o-2′-(1′,3′-d ioxo-
la n e)-7a -m et h ylp er h yd r oin d en -3a -ol (49) a n d (1R,3a S,
7a R )-1-H yd r oxym e t h yl-5-sp ir o-2′-(1′,3′-d ioxola n e )-7a -
m et h ylp er h yd r oin d en -3a -ol (50). A 1 M BH3 solution in
THF (0.390 L, 0.39 mol) was dropped into a solution of 48 in
THF (0.76 L), maintained at 0 °C under N2. After being stirred
(1S,3a R,7a R)-1-H yd r oxym et h yl-7a -m et h ylp er h yd r o-
in d en e-3a -ol (55). To a solution of 54 (1.24 g, 4.5 mmol) in
EtOH (125 mL) was added Raney-Ni (103 g), and the mixture
was heated at reflux for 16 h. After cooling to room temper-
ature, the precipitate was filtered off and the organic solvent
evaporated to dryness to give 55 (0.61 g, 75%) as a white solid,

202 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 1
Cerri et al.
mp 112-114 °C. 1H NMR (CDCl3) δ 1.01 (s, 3H, CH3), 3.52
(dd, 1H, CHHOH), 3.79 (dd, 1H, CHHOH).
aqueous 10% NaH2PO4, dried over Na2SO4, and evaporated
to give (1S,3aS,5R,7aR)-1-hydroxymethyl-5-benzyl-7a-meth-
ylperhydroinden-3a-ol (0.18 g, 100%) as an oil. 1H NMR
(CDCl3) δ 0.92 (s, 3H, CH3), 2.56 (m, 2H, CH2Ph), 3.48 (dd,
1H, CHHOH), 3.77 (dd, 1H, CHHOH), 7.20 (m, 5H, Ph).
To a solution of the above-described 1-hydroxymethyl de-
rivative (0.18 g, 0.70 mmol) in DMSO (2 mL) was added IBX
(0.28 g, 1 mmol). After the mixture was stirred for 1 h, the
aldehyde solution was directly dropped into the buffered
solution at pH 4.5 containing the aminoalkoxyamine to give
7.
(1S,3a R,7a R)-3a -Hyd r oxy-7a -m eth ylp er h yd r oin d en e-
1-ca r boxa ld eh yd e (56). A mixture of 55 (0.30 g, 1.6 mmol)
and IBX (0.69 g, 2.5 mmol) in THF (30 mL) was heated at
reflux for 2.5 h. After cooling to room temperature, the
precipitate was filtered off, and the aldehyde solution was
directly dropped into the solution at pH 4.5 containing the
aminoalkoxyamine to give 2.
(1S,3a S,7a R)-1-Hyd r oxym eth yl-5-[(E)-ben zylid en ]-7a -
m eth ylp er h yd r oin d en -3a -ol (57) a n d (1S,3a S,7a R)-1-Hy-
dr oxym eth yl-5-[(Z)-ben zyliden ]-7a-m eth ylper h ydr oin den -
3a -ol (58). To a mixture of benzyltriphenylphosphonium
bromide and sodium amide (7.50 g, 0.015 mol) in THF (40 mL)
was dropped a solution of 51 (2.16 g, 0.01 mol) in THF (20
mL). After 16 h, 10% aqueous NaH2PO4 was added, and the
resulting mixture was extracted with EtOAc (3×). The com-
bined organic layers were dried over Na2SO4 and evaporated
to dryness. The crude product was purified by flash chroma-
tography (n-hexane/CHCl3/acetone, 4:3:3) to give the (E) isomer
57 (0.51 g, 20%) and the (Z) isomer 58 (0.26 g, 10%) as white
foams, together with an unseparated E/Z mixture (0.40 g,
25%). (E) isomer 57: 1H NMR (CDCl3) δ 1.14 (s, 3H, CH3),
3.56 (dd, 1H, CHHOH), 3.79 (dd, 1H, CHHOH), 6.40 (s, 1H,
CHPh), 7.28 (m, 5H, Ph). (Z) isomer 58: 1H NMR (CDCl3) δ
1.12 (s, 3H, CH3), 3.57 (dd, 1H, CHHOH), 3.79 (dd, 1H,
CHHOH), 6.31 (s, 1H, CHPh), 7.28 (m, 5H, Ph).
(1S,3a S,7a R)-5-(E)-Ben zylid en -3a -h yd r oxy-7a -m et h -
ylp er h yd r oin d en e-1-ca r boxa ld eh yd e (59). A solution of
IBX (0.62 g, 2.2 mmol) in DMSO (4.4 mL) was added to a flask
containing 57 (0.40 g, 1.4 mmol). After 1.5 h, water (5 mL)
was added, the precipitate was filtered off and washed with
Et2O, and the organic solvent was evaporated to dryness to
give 59 (0.13 g, 33%) as a white foam. 1H NMR (CDCl3) δ 1.10
(s, 3H, CH3), 6.29 (s,1H, CHPh), 7.28 (m, 5H, Ph), 9.72 (d, 1H,
CHO, J ) 3.8).
(1S,3a S,5S,7a R)-3a -H yd r oxy-5-b en zyl-7a -m et h ylp er -
h yd r oin d en e-1-ca r boxa ld eh yd e (64). Prepared as described
for 63 starting from 62 to give (1S,3aS,5S,7aR)-1-hydroxy-
methyl-5-benzyl-7a-methylperhydroinden-3a-ol (0.26 g, 100%)
1
as an oil. H NMR (CDCl3) δ 0.81 (s, 3H, CH3), 2.51 (m, 2H,
CH2Ph), 3.51 (dd, 1H, CHHOH), 3.72 (dd, 1H, CHHOH), 7.2
(m, 5H, Ph).
The above-described 1-hydroxymethyl derivative (0.26 g, 1.0
mmol) was dissolved in a solution of IBX (0.47 g, 1.7 mmol) in
DMSO (3 mL). After 1 h water was added and the white
precipitate was filtered off. The aqueous phase was extracted
with EtOAc. The combined extracts were dried over Na2SO4
and evaporated to give 64 (0.26 g, 100%) as an oil. 1H NMR
(CDCl3) δ 0.90 (s, 3H, CH3), 2.53 (d, 2H, CH2Ph), 2.89 (m, 1H
CHCHO), 7.20 (m, 5H, Ph), 9.72 (d, 1H, CHO).
(1S,3aS,5R,7aR)-1-Hydr oxym eth yl-5-cycloh exylm eth yl-
7a -m eth ylp er h yd r oin d en -3a -ol (65). A mixture of 61 (0.37
g, 0.95 mmol) and 5% Rh on alumina (0.25 g) in MeOH (10
mL) was hydrogenated in a Parr apparatus at 4.3 atm for 3 h.
After this time the catalyst was filtered through a Celite pad
and the solution evaporated to give (1S,3aS,5R,7aR)-1-tert-
butyldimethylsilyloxymethyl-5-cyclohexylmethyl-7a-methyl-
1
perhydroinden-3a-ol (0.31 g, 83%) as a white foam. H NMR
(CDCl3) δ 0.14 (s, 6H, Si(CH3)2), 0.94 (s, 9H, C(CH3)3), 0.99 (s,
3H, CH3), 3.47 (dd, 1H, CHHOSi), 3.76 (dd, 1H, CHHOSi).
A solution of the compound above-described (0.31 g, 7.8
mmol) in dioxane/water 1/1 was brought to pH 1 with 3 N HCl
(15 mL) and was stirred for 2 h. The mixture was neutralized
with 5% aqueous Na2HPO4 and extracted with EtOAc (3×).
The combined organic phases were washed with 5% aqueous
NaH2PO4, dried over Na2SO4, and evaporated to give 65 (0.22
g, 100%) as a glassy solid. 1H NMR (CDCl3) δ 1.01 (s, 3H, CH3),
3.49 (dd, 1H, CHHOH), 3.79 (dd, 1H, CHHOH).
(1S,3a S,5R,7a R)-3a -H yd r oxy-5-cycloh exylm et h yl-7a -
m eth ylp er h yd r oin d en e-1-ca r boxa ld eh yd e (66). Prepared
by oxidation with IBX as described for compound 64, starting
from compound 65 (0.22 g, 7.8 mmol) to give 66 (0.18 g, 83%)
as a white foam. 1H NMR (CDCl3) δ 1.04 (s, 3H, CH3), 2.48
(m,1H, CHCHO), 9.74 (d, 1H, CHO).
(1S,3a S,7a R)-5-(Z)-Ben zylid en -3a -h yd r oxy-7a -m eth yl-
p er h yd r oin d en e-1-ca r boxa ld eh yd e (60). Prepared as de-
scribed for compound 59, starting from compound 58 to give
1
60 (0.24 g, 98%) as a white foam. H NMR (CDCl3) δ 1.15 (s,
3H, CH3), 6.44 (s,1H, CHPh), 7.28 (m, 5H, Ph), 9.78 (d, 1H, J
) 3.8, CHO).
(1S,3a S,5R,S,7a R)-1-ter t-Bu tyld im eth ylsilyloxym eth yl-
5-ben zyl-7a-m eth ylper h ydr oin den -3a-ol (61) an d (1S,3aS,
5S,S,7a R)-1-ter t-Bu tyld im eth ylsilyloxym eth yl-5-ben zyl-
7a -m eth ylp er h yd r oin d en -3a -ol (62). A mixture of 57 and
58 (0.63 g, 2.3 mmol) was dissolved in EtOAc (10 mL), and
10% Pd/C (0.045 g) was added. After 1.5 h under H2 at
atmospheric pressure, the catalyst was filtered off and the
organic solvent evaporated to give a 1/1 mixture of (1S,3aS,
5R,7aR)-1-hydroxymethyl-5-benzyl-7a-methylperhydroinden-
3a-ol and (1S,3aS,5S,7aR)-1-hydroxymethyl-5-benzyl-7a-
methylperhydroinden-3a-ol (0.60 g, 95%) as an oil.
To a solution of the above mixture (0.60 g, 2.2 mmol) in DMF
(9 mL) were added tert-butyldimethylsilyl chloride (0.36 g, 2.4
mmol) and imidazole (0.33 g, 4.8 mmol). After being stirred
for 16 h at room temperature, the mixture was poured into
water and extracted with Et2O (3×). The combined organic
layers were washed with water, dried over Na2SO4, and
evaporated to dryness. The crude product was purified by flash
chromatography (n-hexane/Et2O, 9:1) to give 61 (0.26 g, 32%)
and 62 (0.32 g, 38%) as white foams. Isomer 61: 1H NMR
(CDCl3) δ 0.10 (s, 6H, Si(CH3)2), 0.92 (s, 9H, C(CH3)3), 0.98 (s,
3H, CH3), 2.55 (m, 2H, CH2Ph), 3.45 (dd, 1H, CHHOSi), 3.75
(dd, 1H, CHHOSi), 7.10-7.40 (m, 5H, Ph). Isomer 62: 1H NMR
(CDCl3) δ 0.10 (s, 6H, Si(CH3)2), 0.80 (s, 3H, CH3), 0.92 (s, 9H,
C(CH3)3), 2.52 (m, 2H, CH2Ph), 3.47 (dd, 1H, CHHOSi), 3.62
(dd, 1H, CHHOSi), 7.10-7.30 (m, 5H, Ph).
(1S,3aS,5S,7aR)-1-Hydr oxym eth yl-5-cycloh exylm eth yl-
7a -m eth ylp er h yd r oin d en -3a -ol (67). Prepared as described
for compound 65, starting from compound 62 (0.68 g, 1.7 mmol)
to give (1S,3aS,5S,7aR)-1-tert-butyldimethylsilyloxymethyl-5-
cyclohexylmethyl-7a-methylperhydroinden-3a-ol (0.67 g, 100%)
as a white foam. 1H NMR (CDCl3) δ 0.09 (s, 6H, Si(CH3)2),
0.82 (s, 9H, C(CH3)3), 0.90 (s, 3H, CH3), 2.30 (m, 1H, CHCH2O),
3.48 (dd 1H, CHHOSi), 3.63 (dd, 1H, CHHOSi). Subsequent
hydrolysis (dioxane/water at pH 1) gave 67 (0.42 g, 89%) as a
1
glassy oil. H NMR (CDCl3) δ 0.90 (s, 3H, CH3), 2.29 (m,1H,
CHCH2O), 3.50 (dd 1H, CHHOH), 3.70 (dd, 1H, CHHOH).
(1S,3a S,5S,7a R)-3a -H yd r oxy-5-cycloh exylm et h yl-7a -
m et h ylp er h yd r oin d en e-1-ca r b oxya ld eh yd e (68). Pre-
pared as described for compound 64 starting from compound
67 (0.20 g, 0.7 mmol) to give 68 (0.2 g, 100%) as an oil. 1H
NMR (CDCl3) δ 0.92 (s, 3H, CH3), 2.89 (m,1H, CHCHO), 9.72
(d, 1H, J ) 1.9, CHO).
(1S,3a S,5S,7a R)-1-H yd r oxym et h yl-5-p h en yl-7a -m et h -
ylp er h yd r oin d en -3a ,5-d iol (69). To a solution of 51 (20.0 g,
0.10 mol) in dry THF (0.2 L) maintained at -78 °C under
nitrogen, was added a solution of 2 M phenyllithium in
cyclohexane/ether 70/30 (0.213 L, 0.426 mol) dropwise. After
1 h the mixture was raised to 0 °C, and the solution was
treated with 5% aqueus NaH2PO4 and extracted with EtOAc.
(1S,3a S,5R,7a R)-3a -H yd r oxy-5-b en zyl-7a -m et h ylp er -
h yd r oin d en e-1-ca r boxa ld eh yd e (63). A solution of 61 (0.26
g, 0.7 mmol) in dioxane/water 1/1 previously brought to pH 1
with 3 N HCl (9 mL) was stirred for 0.45 h. The mixture was
neutralized with 5% aqueous NaHCO3 and extracted with
EtOAc (3×). The combined organic extracts were washed with

1-(O-Aminoalkyloximes) of Perhydroindene Derivatives
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 1 203
The organic phase was dried over Na2SO4 and evaporated. The
crude product was purified by flash chromatography (n-
hexane/acetone/CHCl3, 4:3:3) to give 69 (22.6 g, 82%) as a white
foam. 1H NMR (CDCl3) δ 1.12 (s, 3H, CH3), 2.91 (m, 1H,
CHCH2O), 3.25 (br, 1H, OH), 3.58 (dd, 1H, CHHOH), 3.81 (dd,
1H, CHHOH), 7.23-7.53 (m, 5H, Ph). 13C NMR (CDCl3) δ 14.5
(q), 22.2 (t), 34.4 (t), 35.8 (t), 37.7 (t), 44.2 (t), 46.2 (s), 50.5 (s),
62.8 (t), 74.7 (s), 81.6 (s), 124.4 (d), 127.0 (d), 128.3 (d), 149.0
(s).
was hydrogenated at 4.3 atm for 4 h. After this time the
catalyst was filtered off through a Celite pad and the solution
evaporated to give 74 (12.30 g, 100%) as an oil. 1H NMR
(CDCl3) δ 1.00 (s, 3H, CH3), 2.7-3.7 (br, 2H, OH), 3.50 (dd,
1H, CHHOH), 3.79 (dd, 1H, CHHOH).
(1S,3a S,5S,7a R)-3a -H yd r oxy-5-cycloh exyl-7a -m et h yl-
p er h yd r oin d en e-1-ca r boxa ld eh yd e (75). Prepared as de-
scribed for compound 73 starting from compound 74 (12 g,
0.046 mol) to give 75 (11.90 g, 100%) as a white foam. The
crude product was sufficiently pure to be used in the next step
(1S,3aS,5R,7aR)-1-Hyd r oxym eth yl-5-p h en yl-7a -m eth yl-
p er h yd r oin d en -3a -ol (70). A mixture of 69 (0.64 g, 2.31
mmol) and 5% Pd/C (0.64 g) in a solution (10 mL) of HClO4 in
EtOAc (1 drop of 70% HClO4 in 60 mL of EtOAc) was
hydrogenated for 2 h at atmospheric pressure. After this time
the catalyst was filtered off through a Celite pad, and the
solution was washed with 5% NaHCO3. The aqueous layer was
extracted with EtOAc (3×). The combined organic layers were
dried over Na2SO4 and evaporated to give an approximately
3:1 mixture of 70 and 72 (0.53 g, 88%) as an oil. Compounds
70 and 72 were separated by flash chromatography (n-hexane/
EtOAc 95/5) of their 1-tert-butyldimethylsilyl ethers (pre-
pared as described for compounds 61 and 62) to give
(1S,3aS,5R,7aR)-1-tert-butyldimethylsilyloxymethyl-5-phenyl-
7a-methylperhydroinden-3a-ol (0.32 g, 48%) and (1S,3aS,
5S,7aR)-1-tert-butyldimethylsilyloxymethyl-5-phenyl-7a-meth-
ylperhydroinden-3a-ol (0.10 g, 16%). (5S) isom er : 1H NMR
(CDCl3) δ 0.15 (s, 6H, Si(CH3)2), 0.95 (s, 9H, C(CH3)3), 1.10 (s,
3H, CH3), 2.25 (m,1H, CHCH2O), 2.72 (m, 1H, CHPh), 3.50
(m, 1H, CHHOSi), 3.63 (m, 1H, CHHOSi), 7.20-7.35 (m, 5H,
Ph). (5R) isom er : 1H NMR (CDCl3) δ 0.10 (s, 6H, Si(CH3)2),
0.90 (s, 3H, CH3), 0.92 (s, 9H, C(CH3)3), 2.44 (m,1H, CHCH2O),
2.83 (m, 1H, CHPh), 3.52 (dd, 1H, CHHOSi), 3.69 (dd, 1H,
CHHOSi), 7.18-7.40 (m, 5H, Ph).
1
without further purification. H NMR (CDCl3) δ 1.00 (s, 3H,
CH3), 9.73 (d, 1H, CHO).
(1S,3a S,5S,7a R)-1-H yd r oxym e t h yl-5-(3-ter t-b u t yld i-
m e t h y ls ily lo x y m e t h y lp h e n y l)-7a -m e t h y lp e r h y d r o -
in d en -3a ,5-d iol (76). To a solution of 1-bromo-3-[(tert-butyl-
dimethylsilyl)oxymethyl]benzene (15.5 g, 0.051 mol) (prepared
following the preparation of 1-bromo-3-[(tert-butyldimethyl-
silyl)oxy]benzene in ref 26) in Et2O (20 mL) and THF (30 mL)
maintained at -78 °C was dropped 1.6 M n-butyllithium in
hexane (32.8 mL, 0.051 mol). After the mixture was stirred
for 1.5 h, a solution of 51 (1.6 g, 8.6 mmol) in THF (10 mL)
was dropped. After 1.5 h at -78 °C, water was added, and the
mixture was extracted with EtOAc (3 ×). The organic phase
was dried over Na2SO4 and evaporated. The crude product was
purified by flash chromatography (n-hexane/acetone/CHCl3,
6:2:2) to give 76 (2.5 g, 70%) as a white foam. 1H NMR (CDCl3)
δ 0.12 (s, 6H, Si(CH3)2), 0.95 (s, 9H, C(CH3)3), 1.10 (s, 3H, CH3),
3.55 (m, 1H, CHHO), 3.80 (m, 1H, CHHO), 4.78 (s, 2H,
OCH2Ar), 7.20-7.52 (m, 4H, Ar).
(1S,3a S,5S,7a R)-1-H yd r oxym e t h yl-5-(4-ter t-b u t yld i-
m e t h y ls ily lo x y m e t h y lp h e n y l)-7a -m e t h y lp e r h y d r o -
in d en -3a ,5-d iol (77). Prepared as described for compound 76
using 1-bromo-4-[(tert-butyldimethylsilyl)oxymethyl]benzene
instead of 1-bromo-3-[(tert-butyldimethylsilyl)oxymethyl]-
benzene. The crude product was purified by flash chromatog-
raphy (n-hexane/acetone/CHCl3, 4:3:3) to give 77 (3.2 g, 65%)
as a white foam. 1H NMR (CDCl3) δ 0.10 (s, 6H, Si(CH3)2),
0.94 (s, 9H, C(CH3)3), 1.10 (s, 3H, CH3), 3.55 (m, 1H, CHHO),
3.80 (m, 1H, CHHO), 4.72 (s, 2H, OCH2Ar), 7.32 (m, 2H, Ar),
7.48 (m, 2H, Ar).
Compound 70 was prepared by hydrolysis, in quantitative
yield, as described for compound 65, starting from (1S,3aS,
5R,7aR)-1-tert-butyldimethylsilyloxymethyl-5-phenyl-7a-meth-
ylperhydroinden-3a-ol (0.30 g). 1H NMR (CDCl3) δ 0.90 (s, 3H,
CH3), 2.45 (m, 1H, CHCH2O), 2.83 (m, 1H, W1/2h ) 25 Hz,
CHPh), 3.57 (dd, 1H, CHHOH) 3.78 (dd, 1H, CHHOH), 7.15-
7.35 (m, 5H, Ph).
(1S,3a S,5R,7a R)-5-P h en yl-3a -h yd r oxy-7a -m et h ylp er -
h yd r oin d en e-1-ca r boxa ld eh yd e (71). Prepared by oxidation
with IBX as described for compound 64 starting from com-
pound 70 (0.20 g, 0.8 mmol) to give 71 in quantitative yield.
1H NMR (CDCl3) δ 1.00 (s, 3H, CH3), 2.90 (m, 1H, CHPh), 3.02
(m, 1H, CHCHO), 7.18-7.35 (m, 5H, Ph), 9.75 (d, 1H, CHO).
(1S,3a S,5S,7a R)-1-Hyd r oxym eth yl-5-p h en yl-7a -m eth yl-
p er h yd r oin d en -3a -ol (72). A mixture of 69 (22.6 g, 0.082
mol) and 50% Raney-Ni suspension in water (22.6 g) in EtOH
(67 mL) was heated at reflux for 3 h. After cooling to room
temperature, the mixture was filtered through a Celite pad
and the solution evaporated to give 72 (17.48 g, 82%) as a
white foam. 1H NMR (CDCl3) δ 1.12 (s, 3H, CH3), 2.31 (m, 1H,
CHCH2O), 2.73 (m, 1H, W1/2h ) 25 Hz, CHPh), 3.53 (dd, 1H,
CHHOH), 3.81 (dd, 1H, CHHOH), 3.85 (br, 1H, OH), 7.17-
7.45 (m, 5H, Ph). 13C NMR (CDCl3) δ 14.9 (q), 22.1 (t), 29.8
(t), 39.5 (t), 40.1 (t), 40.1 (t), 41.6 (d), 46.5 (s), 51.1 (d), 62.3 (t),
81.7 (s), 125.9 (d), 125.9 (d), 126.1 (d), 128.4 (d), 128.4 (d), 146.1
(s).
(1S,3a S,5S,7a R)-3a -H yd r oxy-5-p h en yl-7a -m et h ylp er -
h yd r oin d en e-1-ca r boxa ld eh yd e (73). To a 0.5 M solution
of IBX (1.3 g, 4.6 mmol) in DMSO was added 72 (1.00 g, 3.8
mmol). After 1.5 h water was added, and the white precipitate
was filtered off. The aqueous phase was extracted with EtOAc.
The organic phase was dried over Na2SO4 and evaporated to
give 73 (1.00 g, 100%) as an oil. 1H NMR (CDCl3) δ 1.15 (s,
3H, CH3), 2.75 (m, 1H, CHPh), 7.18-7.38 (m, 5H, Ph), 9.78
(d, 1H, CHO). 13C NMR (CDCl3) δ 16.1 (q), 20.7 (t), 28.9 (t),
36.4 (t), 38.7 (t), 40.1 (t), 41.6 (d), 49.3 (s), 61.7 (d), 82.5 (s),
126.3 (d), 126.8 (d), 126.8 (d), 128.5 (d), 128.5 (d), 145.5 (s),
206.6 (d).
(1S,3a S,5S,7a R)-1-Hyd r oxym eth yl-5-(3-m eth ylp h en yl)-
7a -m eth ylp er h yd r oin d en -3a -ol (78) and (1S,3a S,5S,7a R)-
1-Hyd r oxym et h yl-5-(3-ter t-b u t yld im et h ylsilyloxym et h -
ylp h en yl)-7a -m eth ylp er h yd r oin d en -3a -ol (80). A mixture
of 76 (1.30 g, 3.3 mmol) and aqueuos Raney-Ni (ca 100 g) in
EtOH (50 mL) was heated at reflux under vigorous stirring
for 3 days. After cooling to room temperature, the mixture was
filtered through a Celite pad and the solution evaporated. The
crude product was purified by flash chromatography (cyclo-
hexane/EtOAc 7:3 to 1:1) to give 78 (0.36 g, 40%) and 80 (0.32
g, 26%) as thick oils. 78: 1H NMR (CDCl3) δ 1.12 (s, 3H, CH3),
2.35 (s, 3H, CH3), 2.70 (m, 1H, CHAr), 3.54 (dd, 1H, CHHOH),
3.82 (dd, 1H, CHHOH), 7.00-7.25 (m, 4H, Ar). 80: 1H NMR
(CDCl3) δ 0.11 (s, 6H, Si(CH3)2), 0.94 (s, 9H, C(CH3)3), 1.12 (s,
3H, CH3), 2.72 (m, 1H, CHPh), 3.55 (dd, 1H, CHHOH), 3.81
(dd, 1H, CHHOH), 4.72 (s, 2H, OCH2Ar), 7.10-7.35 (m, 4H,
Ar).
(1S,3a S,5S,7a R)-1-Hyd r oxym eth yl-5-(4-m eth ylp h en yl)-
7a -m eth ylp er h yd r oin d en -3a -ol (79) and (1S,3a S,5S,7a R)-
1-Hyd r oxym et h yl-5-(4-ter t-b u t yld im et h ylsilyloxym et h -
ylp h en yl)-7a -m eth ylp er h yd r oin d en -3a -ol (81). Prepared
as described for compound 78 and 80, starting from 77 (3.2 g,
0.0078 mol). The crude product was purified by flash chroma-
tography (n-hexane/acetone/CHCl3, 6:2:2) to give 79 (0.89 g,
42%) and 81 (1.21 g, 40%) as thick oils. 79: 1H NMR (CDCl3)
δ 1.11 (s, 3H, CH3), 2.35 (s, 3H, CH3), 2.70 (m, 1H, CHAr),
3.55 (dd, 1H, CHHOH), 3.82 (dd, 1H, CHHOH), 7.12 (m, 4H,
Ar). 81: 1H NMR (CDCl3) δ 0.11 (s, 6H, Si(CH3)2), 0.92 (s, 9H,
C(CH3)3), 1.12 (s, 3H, CH3), 2.71 (m, 1H, CHAr), 3.55 (dd, 1H,
CHHOH), 3.81 (dd, 1H, CHHOH), 4.72 (s, 2H, OCH2Ar), 7.18-
7.32 (m, 4H, Ar).
(1S ,3a S ,5S ,7a R )-1-H yd r oxym e t h yl-5-cycloh e xyl-7a -
m eth ylp er h yd r oin d en -3a -ol (74). A mixture of 72 (12.0 g,
0.046 mol) and 5% Rh on alumina (5.1 g) in MeOH (0.18 L)
(1S,3a S,5S,7a R)-5-(3-Me t h ylp h e n yl)-3a -h yd r oxy-7a -
m eth ylp er h yd r oin d en e-1-ca r boxa ld eh yd e (82), (1S,3a S,
5S,7a R)-5-(4-Met h ylp h en yl)-3a -h yd r oxy-7a -m et h ylp er -

204 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 1
Cerri et al.
h yd r oin d en e-1-ca r boxa ld eh yd e (83), (1S,3a S,5S,7a R)-5-
(3-ter t-Bu tyld im eth ylsilyloxym eth ylp h en yl)-3a -h yd r oxy-
7a -m eth ylp er h yd r oin d en e-1-ca r boxa ld eh yd e (84) a n d
(1S,3a S,5S,7a R)-5-(4-ter t-Bu t yld im et h ysilyloxym et h yl-
ph en yl)-3a -h ydr oxy-7a -m eth ylp er h ydr oin d en e-1-ca r box-
a ld eh yd e (85). Prepared as described for compound 73 to give
82 (0.27 g, 89%), 83 (0.43 g, 100%), 84 (0.27 g, 95%), 85 (0.60
g, 97%) as oils. 82: 1H NMR (CDCl3) δ 1.15 (s, 3H, CH3), 2.34
(s, 3H, CH3), 2.44 (m, 1H, CHCHO), 2.70 (m, 1H, CHAr), 7.00-
7.29 (m, 4H, Ar), 9.78 (d, 1H, CHO). 83: 1H NMR (CDCl3) δ
1.12 (s, 3H, CH3), 2.33 (s, 3H, CH3), 2.45 (m, 1H, CHCHO),
2.72 (m, 1H, CHAr), 7.12 (m, 4H, Ar), 9.78 (d, 1H, CHO). 84:
1H NMR (CDCl3) δ 0.12 (s, 6H, Si(CH3)2), 0.95 (s, 9H, C(CH3)3),
1.17 (s, 3H, CH3), 2.45 (m, 1H, CHCHO), 2.74 (m, 1H, CHAr),
4.72 (s, 2H, OCH2Ar), 7.08-7.30 (m, 4H, Ar), 9.78 (d, 1H, J )
4.3, CHO). 85: 1H NMR (CDCl3) δ 0.12 (s, 6H, Si(CH3)2), 0.94
(s, 9H, C(CH3)3), 1.17 (s, 3H, CH3), 2.45 (m, 1H, CHCHO), 2.72
(m, 1H, CHAr), 4.72 (s, 2H, OCH2Ar), 7.16-7.30 (m, 4H, Ar),
9.78 (d, 1H, CHO).
(1S ,3a S ,5S ,7a R )-1-H yd r oxym e t h yl-5-(3-p yr id yl)-7a -
m eth ylp er h yd r oin d en -3a -ol (90), (1S,3a S,5S,7a R)-1-Hy-
d r oxym eth yl-5-(4-p yr id yl)-7a -m eth ylp er h yd r oin d en -3a -
ol (91), (1S,3a S,5S,7a R)-1-Hyd r oxym eth yl-5-(3-ter t-bu tyl-
d im eth ylsilyloxyp h en yl)-7a -m eth ylp er h yd r oin d en -3a -ol
(92), a n d (1S,3a S,5S,7a R)-1-Hyd r oxym eth yl-5-(4-ter t-bu -
t yld im et h ylsilyloxyp h en yl)-7a -m et h ylp er h yd r oin d en -
3a -ol (93). The appropriate starting material was dissolved
in EtOH, and Raney-Ni (1:10, w/w) was added. After being
stirred at reflux for 8 h, the mixture was filtered through a
Celite pad and the solvent evaporated to dryness. The crude
products were purified by flash chromatography (CHCl3/
MeOH, 95:5) to give 90 (0.18 g, 23%) as a white foam; (CHCl3/
MeOH/26%w/v aqueous NH3, 95:5:0.5) to give 91 (0.03 g, 5%)
as a white foam; (cyclohexane/EtOAc, 7:3) to give 92 (0.84 g,
66%) as a white foam; (CHCl3/Et2O, 7:3) to give 93 (0.66 g,
53%) as a white foam. 90: 1H NMR (CDCl3) δ 1.12 (s, 3H, CH3),
2.74 (m, 1H, CHPy), 3.54 (dd, 1H, CHHOH), 3.80 (dd, 1H,
CHHOH), 7.25 (m, 1H, Py), 7.58 (m, 1H, Py), 8.45 (m, 2H, Py).
91: 1H NMR (CDCl3) δ 1.12 (s, 3H, CH3), 2.70 (m, 1H, CHPy),
3.55 (m, 1H, CHHOH), 3.80 (m, 1H, CHHOH), 7.12 (m, 2H,
Py), 8.50 (m, 2H, Py). 92: 1H NMR (CDCl3) δ 0.22 (s, 6H, Si-
(CH3)2), 1.00 (s, 9H, C(CH3)3), 1.12 (s, 3H, CH3), 2.68 (m, 1H,
CHAr), 3.53 (dd, 1H, CHHOH) 3.81 (dd, 1H, CHHOH), 6.65-
7.20 (m, 4H, Ar). 93: 1H NMR (CDCl3) δ 0.22 (s, 6H, Si(CH3)2),
0.98 (s, 9H, C(CH3)3), 1.12 (s, 3H, CH3), 2.68 (m, 1H, CHAr),
3.53 (m, 1H, CHHOH) 3.80 (m, 1H, CHHOH), 6.78 (m, 2H,
Ar), 7.08 (m, 2H, Ar).
(1S,3aS,5S,7aR)-1-Hydr oxym eth yl-5-(3-pyr idyl)-7a-m eth -
ylp er h yd r oin d en -3a ,5-d iol (86). To a solution of 1.6 M
n-butyllithium in hexane (44.19 mL, 0.07 mol) in Et2O (40 mL)
maintained at -40 °C was dropped 3-bromopyridine (6.86 mL,
0.07 mol). After 1 h the mixture was cooled to -78 °C, and a
solution of 51 (1.4 g, 0.007 mol) in THF (40 mL) was dropped.
After 1.5 h the mixture was allowed to warm to room
temperature, and a saturated water solution of NH4Cl was
added. The aqueous phase was extracted with CH2Cl2/EtOH
9:1 (3×). The combined organic layers were dried over Na2SO4
and evaporated to give 86 (1.94 g, 100%) as an oil. 1H NMR
(CDCl3) δ 1.12 (s, 3H, CH3), 3.55 (m, 1H, CHHOH), 3.81 (m,
1H, CHHOH), 7.28 (m, 1H, Py), 7.85 (m, 1H, Py), 8.50 (m, 1H,
Py), 8.78 (m, 1H, Py).
(1S,3a S,5S,7a R)-5-(3-P yr id yl)-3a -h yd r oxy-7a -m et h yl-
p er h yd r oin d en e-1-ca r boxa ld eh yd e (94). To solution of 90
(0.18 g, 0.69 mmol) in DMSO (2 mL) was added IBX (0.29 g,
1.03 mmol). After the mixture was stirred for 1 h, the aldehyde
solution was directly dropped into the appropriate buffered
solution at pH 4.5 containing the aminoalkoxyamine.
(1S,3aS,5S,7aR)-1-Hydr oxym eth yl-5-(4-pyr idyl)-7a-m eth -
ylp er h yd r oin d en -3a ,5-d iol (87). Prepared as described for
compound 86 starting from 4-bromopyridine (8.4 g, 0.052 mol)
and 51 (0.80 g, 4.0 mmol). The crude product was purified by
flash chromatography (CH2Cl2/MeOH, 93:7 to 8:2) to give 87
(0.86 g, 77%) as a white foam. H NMR (DMSO-d6) δ 0.98 (s,
3H, CH3), 3.40 (m, 2H, CH2O), 4.64 (s, 1H, OH), 4.90 (t, 1H,
OH), 5.10 (s, 1H, OH), 7.44 (m, 2H, Py), 8.46 (m, 2H, Py).
(1S,3a S,5S,7a R)-5-(4-P yr id yl)-3a -h yd r oxy-7a -m et h yl-
p er h yd r oin d en e-1-ca r boxa ld eh yd e (95). To solution of 91
(0.030 g, 0.1 mmol) in THF (2 mL) was added IBX (0.042 g,
0.15 mmol). The mixture was heated at reflux for 1.5 h. After
cooling to room temperature, the aldehyde solution was
directly dropped into the appropriate buffered solution at pH
4.5 containing the aminoalkoxyamine.
1
(1S,3aS,5S,7aR)-5-(3-ter t-Bu tyldim eth ylsilyloxyph en yl)-
3a -h yd r oxy-7a -m e t h ylp e r h yd r oin d e n e -1-ca r b oxa ld e -
h yd e (96) a n d (1S,3a S,5S,7a R)-5-(4-ter t-Bu tyld im eth yl-
silyloxyph en yl)-3a-h ydr oxy-7a-m eth ylper h ydr oin den e-1-
ca r boxa ld eh yd e (97). Prepared as described for compound
73 to give 96 (100%) and 97 (100%) as oils. The crude products
were used in the next step without further purification. 96:
1H NMR (CDCl3) δ 0.21 (s, 6H, Si(CH3)2), 1.00 (s, 9H, C(CH3)3),
1.12 (s, 3H, CH3), 2.45 (m, 1H, CHCHO), 2.70 (m, 1H, CHAr),
6.70-7.20 (m, 4H, Ar), 9.78 (d, 1H, CHO). 97: 1H NMR (CDCl3)
δ 0.20 (s, 6H, Si(CH3)2), 1.00 (s, 9H, C(CH3)3), 1.12 (s, 3H, CH3),
2.45 (m, 1H, CHCHO), 2.70 (m, 1H, CHAr), 6.78 (m, 2H, Ar),
7.08 (m, 2H, Ar), 9.78 (d, 1H, CHO).
(1S,3a S,5S,7a R)-1-H yd r oxym e t h yl-5-(3-ter t-b u t yld i-
m eth ylsilyloxyph en yl)-7a-m eth ylper h ydr oin den -3a,5-diol
(88). To a solution of 1-bromo-3-[(tert-butyldimethylsilyl)oxy]-
benzene26 (8.80 g, 0.032 mol) in Et2O (45 mL) maintained at
-78 °C was dropped 1.5 M tert-butyllithium in pentane (26
mL, 0.039 mol). After being stirred for 0.5 h at -78 °C and 20
min at 0 °C, the mixture was cooled at -78 °C, and a solution
of 51 (1.00 g, 5.4 mmol) in THF (10 mL) was dropped. After
0.5 h the mixture was allowed to warm to room temperature
and water was added. The aqueous phase was extracted three
times with EtOAc. The combined organic layers were dried
over Na2SO4 and evaporated. The crude product was purified
by flash chromatography (n-hexane/acetone/CHCl3, 6:2:2) to
(1S,3aS,5S,7aR)-1-Hydr oxym eth yl-5-(4-h ydr oxyph en yl)-
7a -m eth ylp er h yd r oin d en -3a -ol (98). A solution of 93 (0.50
g, 1.3 mmol) in dioxane (10 mL) and water (5 mL) was brought
to pH 0.9 with 3 N HCl. After being stirred for 16 h, the
mixture was brought to pH 5 with 5% aqueous Na2HPO4
solution, dioxane was evaporated, and the aqueous phase was
extracted with EtOAc. The organic phase was dried over
Na2SO4 and evaporated to dryness to give 98 (0.24 g, 67%) as
1
give 88 (1.3 g, 61%) as a white foam. H NMR (CDCl3) δ 0.22
(s, 6H, Si(CH3)2), 0.98 (s, 9H, C(CH3)3), 1.12 (s, 3H, CH3), 3.55
(dd, 1H, CHHOH) 3.82 (dd, 1H, CHHOH), 6.70-7.30 (m, 4H,
Ar).
(1S,3a S,5S,7a R)-1-H yd r oxym e t h yl-5-(4-ter t-b u t yld i-
m eth ylsilyloxyph en yl)-7a-m eth ylper h ydr oin den -3a,5-diol
(89). To a solution of 1-bromo-3-[(tert-butyldimethylsilyl)oxy]-
benzene (13.3 g, 0.049 mol; prepared following the method
descibed in ref 26) in n-hexane (100 mL) maintained at 0 °C
was dropped 1.6 M n-butyllithium in hexane (33.7 mL, 0.054
mol). After being stirred at room tempearture for 4 h, the
mixture was cooled at -78 °C and a solution of 51 (1.50 g, 7.6
mmol) in THF (100 mL) was added. After 1.5 h the reaction
was worked up as described for compound 88. To the crude
product was added Et2O, and the precipitated white solid was
collected by filtration to give 89 (1.38 g, 43%). 1H NMR (CDCl3)
δ 0.22 (s, 6H, Si(CH3)2), 0.98 (s, 9H, C(CH3)3), 1.10 (s, 3H, CH3),
3.55 (m, 1H, CHHOH) 3.80 (m, 1H, CHHOH), 6.82 (m, 2H,
Ar), 7.38 (m, 2H, Ar).
1
a white foam. H NMR (CD3OD) δ 1.10 (s, 3H, CH3), 2.65 (m,
1H, CHAr), 3.45 (dd, 1H, CHHOH), 3.70 (dd, 1H, CHHOH),
6.71 (m, 2H, Ar), 7.05 (m, 2H, Ar).
(1S,3aS,5S,7aR)-1-Hydroxymethyl-5-[4-(2-dimethylamino-
eth oxy)p h en yl]-7a -m eth ylp er h yd r oin d en -3a -ol (99). A
mixture of 98 (0.24 g, 0.87 mmol), silver carbonate (0.48 g,
1.74 mmol), and 1-chloro-2-dimethylaminoethane (4 mL) was
stirred at 50 °C in the dark for 6 h. After cooling at room
temperature, the mixture was filtered through a Celite pad
and the pad was washed with toluene/MeOH, 9:1. The organic
solvent was evaporated, and the crude product was purified
by flash chromatography (CHCl3/MeOH, 9:1, CHCl3/MeOH/

1-(O-Aminoalkyloximes) of Perhydroindene Derivatives
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 1 205
26% w/v aqueous NH3, 9:1:0.1) to give 99 (0.13 g, 43%) as an
oil. 1H NMR (CDCl3) δ 1.10 (s, 3H, CH3), 2.35 (s, 6H, N(CH3)2),
2.65 (m, 1H, CHAr), 2.75 (t, 2H, CH2N), 3.50 (dd, 1H,
CHHOH), 3.75 (dd, 1H, CHHOH), 4.05 (t, 2H, CH2O), 6.71 (m,
2H, Ar), 7.05 (m, 2H, Ar).
over Na2SO4, and evaporated to dryness to give (1R,3aS,5S,
7aR)-1-(E)-allyl alcohol-5-cyclohexyl-7a-methylperhydroindene-
3a-ol (3.4 g) as an oil. The crude product was used in the next
step without further purification. H NMR (CDCl3) δ 0.84 (s,
3H, CH3), 2.33 (m, 1H, CHCHd), 4.11 (d, 2H, CH2O), 5.48 (dt,
1H, CHCH2OH), 5.89 (dd, 1H, CHCHd).
To a solution of (1R,3aS,5S,7aR)-1-(E)-allyl alcohol-5-cyclo-
hexyl-7a-methylperhydroindene-3a-ol (3.4 g, 9.7 mmol) in
dioxane (100 mL), maintained at 0-5 °C, was added MnO2
(20.4 g, 0.23 mol). After being stirred for 3 h at room
temperature, the mixture was filtered through a Celite pad.
The filtrate was washed with acetone and the organic solvent
evaporated to dryness to give 105 (3.19 g, 96% from 75). 1H
NMR (CDCl3) δ 0.86 (s, 3H, CH3), 2.49 (m, 1H, CHCHd), 5.92
(dd, 1H, J ) 8.1, CHCHdO) 7.09 (dd, 1H, J ) 10.0, CHCHd),
9.49 (d, 1H, J ) 8.0, CHO).
1
(1S,3aS,5S,7aR)-5-[4-(2-Dim eth ylam in oeth oxy)ph en yl]-
3a -h yd r oxy-7a -m e t h ylp e r h yd r oin d e n e -1-ca r b oxa ld e -
h yd e (100). To a solution of 99 (0.18 g, 0.51 mmol) in THF
(3.5 mL) was added IBX (0.30 g, 1.1 mmol). After being stirred
at reflux for 1 h, the mixture was cooled to room temperature,
diluted with CHCl3, and filtered trough a Celite pad, washing
with THF. The organic solvent was evaporated to give 100
(0.21 g, 100%) as an oil. The crude product contained an
equimolar amount of o-iodoso benzoic acid and was used in
1
the next step without further purification. H NMR (CD3OD)
δ 1.10 (s, 3H, CH3), 2.70 (m, 1H, CHAr), 2.90 (s, 6H, N(CH3)2),
3.50 (t, 2H, CH2N), 4.30 (t, 2H, CH2O), 6.90 (m, 2H, Ar), 7.20
(m, 2H, Ar), 9.68 (d, 1H, CHO).
(1S,3a S,5S,7a R)-1-P r op ion a ld eh yd e-5-cycloh exyl-7a -
m eth ylp er h yd r oin d en e-3a -ol (106). A mixture of 105 (1.0
g, 3.4 mmol) and 5% Pd/C (0.3 g) in EtOH (0.2 L) was
hydrogenated at room temperature for 3 h. After this time the
catalyst was filtered through a Celite pad and washed with
EtOH, and the organic solvent evaporated to give 106 (0.96 g,
(1S,3a S,5S,7a R)-1-Vin yl-5-cycloh exyl-7a -m et h ylp er -
h yd r oin d en -3a -ol (101). The following were added in order
to a solution of 75 (1.93 g, 7.0 mmol) in dry THF (96.5 mL):
methyltriphenylphosphonium bromide (4.64 g, 0.01 mol), tert-
butyl alcohol (0.16 mL, 0.001 mol), and potassium tert-butoxide
(1.63 g, 0.01 mol). After being stirred at room tempearature
for 40 min, the mixture was diluted with 5% aqueous NaH2PO4
solution and extracted with Et2O (3×). The combined organic
layers were dried over Na2SO4 and evaporated to dryness. The
crude product was purified by flash chromatography (n-
hexane/EtOAc, 95:5) to give 101 (0.88 g, 45%) as a white foam.
1H NMR (CDCl3) δ 0.86 (s, 3H, CH3), 4.84 (m, 2H, dCH2), 5.99
(m, 1H, dCH).
1
97%) as a white foam. H NMR (CDCl3) δ 0.94 (s, 3H, CH3),
2.20-2.60 (m, 2H, CH2CHO), 9.76 (t, 1H, CHO).
E t h yl (1R,3a S,5S,7a R)-5-Cycloh exyl-3a -h yd r oxy-7a -
m et h ylp er h yd r oin d en -1-yl-(E)-m et a cr yla t e (107). Pre-
pared as described for compound 104 using the following
amounts of reagents: 55% (dispersion in mineral oil) NaH
(0.54 g, 0.01 mol), THF (45 mL), and triethyl 2-phosphono-
propionate (3.21 mL, 0.01 mol). After the mixture was stirred
at room temperature for 0.5 h and cooled to 0 °C, the aldehyde
was added. At the end 107 was obtained (3.29 g). The crude
product was used in the next step without further purification.
1H NMR (CDCl3) δ 0.81 (s, 3H, CH3), 1.28 (t, 3H, CH2CH3),
1.79 (d, 3H, dCCH3), 2.63 (m, 1H, CHCHd), 4.17 (m, 2H,
OCH2), 6.92 (br d, 1H, CHd).
(1R,3a S,5S,7a R)-1-(E)-Meta cr yla ld eh yd e-5-cycloh exyl-
7a -m eth ylp er h yd r oin d en e-3a -ol (108). To a solution of 107
(2.22 g) in dry THF (50 mL) maintained at -78 °C, under
nitrogen, was dropped 1 M DIBAH in THF (44 mL, 0.044 mol),
in three portions, every hour from the start of the reaction.
After 16 h at room temperature, the mixture was cooled at 0
°C and 1 N H2SO4 (90.26 mL) was added. The jelly-like
suspension was stirred for 1 h and extracted with EtOAc. The
organic phase was dried over Na2SO4 and evaporated to
dryness. The crude product was purified by flash chromatog-
raphy (n-hexane/EtOAc, 7:3) to give (1R,3aS,5S,7aR)-1-(E)-
allyl alcohol-5-cyclohexyl-7a,R-dimethylperhydroindene-3a-ol
(0.89 g, 30% from 75) as a white foam. 1H NMR (CDCl3) δ 0.83
(s, 3H, CH3), 1.68 (d, 3H, dCCH3), 2.55 (m, 1H, CHCHd), 4.03
(br s, 2H, CH2OH), 5.59 (br d, 1H, CHd).
(1S,3a S,5S,7a R)-1-Hyd r oxyeth yl-5-cycloh exyl-7a -m eth -
ylp er h yd r oin d en -3a -ol (102). Prepared as described for
compound 49 using the following amounts of reagents: 1 M
BH3 solution in THF (4.4 mL, 3.4 mmol), 100 (0.88 g, 3.0 mmol)
in THF (22 mL), water (4 mL, 0.39 mol), sodium perborate
(0.92 g, 5.0 mmol), and 4 N NaOH (1.4 mL, 5.0 mmol) to give
102 (0.88 g, 45%) as a white foam. The crude product was used
1
in the next step without purification. H NMR (CDCl3) δ 0.92
(s, 3H, CH3), 3.50-3.75 (m, 2H, CH2O).
(1R,3a S,5S,7a R)-5-Cycloh exyl-r,3a -oxid e-7a -m et h yl-
p er h yd r oin d en e-1-eth a n ol (103). To a solution of 102 (0.89
g, 3 mmol) in DMSO (7.7 mL) was added IBX (1.06 g, 3.7
mmol) over 1 h. When 102 disappeared (NMR), the reaction
mixture was directly dropped into the appropriate buffered
solution at pH 4.5 containing the aminoalkoxyamine. 1H NMR
(DMSO-d6) δ 0.93 (s, 3H, CH3), 5.00 (m, 1H, CHOH), 5.90 (d,
1H, OH).
Meth yl (1R,3a S,5S,7a R)-5-Cycloh exyl-3a -h yd r oxy-7a -
m eth ylp er h yd r oin d en e-1-yl-(E)-a cr yla te (104). To a sus-
pension of NaH (55% dispersion in mineral oil) (1.04 g, 0.024
mol) in dry THF, maintained at 0 °C under nitrogen, was
dropped trimethyl phosphonoacetate (3.89 mL, 0.027 mol).
After the mixture was stirred for 1 h, a solution of 75 (3.00
g, 0.011 mol) in THF (30 mL) was added. After the mixture
was stirred for 2 h at room temperature, 5% aqueous NaH2PO4
was added and the mixture was extracted with EtOAc (3×).
The combined organic layers were dried on Na2SO4 and
evaporated to dryness to give 104 (3.50 g, 100%) as an oil. The
crude product was used in the next step without further
purification. 1H NMR (CDCl3) δ 0.85 (s, 3H, CH3), 2.33 (m,
1H, CHCHd), 3.72 (s, 3H, OCH3), 5.63 (d, 1H, J ) 16.0,
dCHCO), 7.14 (dd, 1H, J ) 10.0, 16.0, CHCHd).
(1R,3a S,5S,7a R)-1-(E)-Acr yla ld eh yd e-5-cycloh exyl-7a -
m eth ylp er h yd r oin d en e-3a -ol (105). To a solution of 104 (4.8
g, 0.015 mol) in dry THF (0.218 L) maintained at -78 °C,
under nitrogen, was dropped 1 M DIBAH in THF (77 mL,
0.077mol). The mixture was allowed to warm to -20 °C, and
DIBAH (33 mL) was added. After being stirred at room
temperature for 16 h, the mixture was cooled to 0 °C, a solution
of citric acid (34.6 g, 0.18 mol) in water (0.3 L) was slowy
added, and the mixture was diluted with Et2O. The jelly-like
suspension was stirred for 1 h and extracted with EtOAc. The
organic phase was washed with 5% aqueous Na2HPO4, dried
Compound 108 (0.85 g, 100%) was prepared as described
for compound 106 using the following amounts of reagents:
(1R,3aS,5S,7aR)-1-(E)-allyl alcohol-5-cyclohexyl-7a,R-dimeth-
ylperhydroindene-3a-ol (0.89 g, 2.0 mmol), MnO2 (6.09 g, 0.07
1
mol), dioxane (23 mL). H NMR (CDCl3) δ 0.86 (s, 3H, CH3),
1.72 (d, 3H, dCCH3), 2.82 (m, 1H, CHdCH), 6.79 (dq, 1H,
CHd), 9.41 (s, 1H, CHO).
(1S,3a S,5S,7a R)-1-Hyd r oxym eth yl-5-(4-cis-ter t-bu tyld i-
methylsilyloxycyclohexyl)-7a-methylperhydroindene-3a-ol
(109). Prepared as described for compound 74 starting from
93 (5.00 g, 0.013 mol), 5% Rh on alumina (7.14 g) in MeOH
(100 mL), in a Parr apparatus for 24 h. The crude product was
purified by flash chromatography (CH2Cl2/2-propanol, 96:4) to
give 109 (2.53 g, 50%) as a white foam. 1H NMR (CDCl3) δ
0.03 (s, 6H, Si(CH3)2), 0.91 (s, 9H, C(CH3)3), 0.99 (s, 3H, CH3),
3.48 (dd, 1H, CHHOH), 3.77 (dd, 1H, CHHOH), 3.92 (m, 1H,
W1/2h ) 10 Hz, TBDMSOCH).
(1S,3a S,5S,7a R)-5-(4-cis-ter t-Bu t yld im et h ylsilyloxy-
cycloh exyl)-3a-h ydr oxy-7a-m eth ylper h ydr oin den e-1-car -
boxa ld eh yd e (110). Prepared as described for compound 73
starting from compound 109 (0.72 g, 2.0 mmol) to give 110
(0.70 g, 100%) as an oil. The crude product was used in the
next step without further purification. 1H NMR (CDCl3) δ 0.05

206 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 1
Cerri et al.
(s, 6H, Si(CH3)2), 0.92 (s, 9H, C(CH3)3), 1.00 (s, 3H, CH3), 3.92
(m, 1H, TBDMSOCH), 9.73 (d, 1H, CHO).
tert-butyldimethylsilyloxy-1-cyclohexyl)-7a-methylperhydro-
indene-3a-ol (0.80 g, 100% from 113) as a white foam. 1H NMR
(CDCl3) δ 0.05 (s, 6H, Si(CH3)2), 0.89 (s, 9H, C(CH3)3), 1.00 (s,
3H, CH3), 3.47 (m, 1H, TBDMSOCH), 3.50 (dd, 1H, CHHOH),
3.78 (dd, 1H, CHHOH).
(1S,3a S,5S,7a R)-1-Acetoxym eth yl-5-(4-cis-ter t-bu tyld i-
m eth ylsilyloxycycloh exyl-7a-m eth ylper h ydr oin den e-3a-ol
(111). To a solution of 109 (1.48 g, 3 mmol) in pyridine (4 mL)
were added DMAP (8 mg) and acetic anhydride (0.4 mL, 4
mmol). After being stirred for 16 h at room temperature, the
mixture was diluted with 5% aqueous NaH2PO4 and extracted
with chloroform. The organic phase was dried over Na2SO4
and evaporated to dryness to give 111 (1.60 g, 100%) as a white
foam. 1H NMR (CDCl3) δ 0.05 (s, 6H, Si(CH3)2), 0.90 (s, 9H,
C(CH3)3), 0.96 (s, 3H, CH3), 2.08 (s, 3H, OAc), 3.92 (m, 1H,
W1/2h ) 10 Hz, TBDMSOCH), 4.06 (dd, 1H, CHHOAc), 4.22
(dd, 1H, CHHOAc).
Compound 115 was oxidized, in quantitative yield, as
described for compound 112 starting from the above-described
1-hydroxymethyl derivative (0.80 g, 2.0 mmol) and IBX (0.68
1
g, 2.0 mmol) in THF (16 mL). H NMR (CDCl3) δ 0.05 (s, 6H,
Si(CH3)2), 0.89 (s, 9H, C(CH3)3), 1.01 (s, 3H, CH3), 3.48 (m,
1H, TBDMSOCH), 9.72 (d, 1H, CHO).
Biology. Na +,K+-ATP a se Bin d in g. The affinity for the
receptor site of Na+,K+-ATPase was evaluated by the displace-
ment of the specific [3H]ouabain binding from Na+,K+-ATPase
receptor24 isolated from dog kidney purified according to
J ørgensen.25 The IC50 values (concentration that inhibits
ouabain binding by 50%) represent the means of values
determined in two to three separate experiments in duplicate
and were calculated using a nonlinear least-squares fitting
algorithm.
(1S,3aS,5S,7aR)-1-Acetoxym eth yl-5-(4-oxo-1-cycloh exyl)-
7a -m eth ylp er h yd r oin d en e-3a -ol (112). A solution of 111
(1.60 g, 3.0 mmol) in a 2/1 dioxane/water solution (24 mL) was
brought to pH 1 with 3 N HCl. After being stirred for 1.5 h at
room temperature, the mixture was neutralized with 5%
Na2HPO4 and extracted with EtOAc. The organic phase was
dried over Na2SO4 and evaporated to dryness. The crude
product was purified by flash chromatography (n-hexane/
chloroform/acetone, 6:2:2) to give (1S,3aS,5S,7aR)-1-acetoxy-
methyl-5-(4-cis-hydroxy-1-cyclohexyl)-7a-methylperhydroindene-
In otr op ic Activity in Gu in ea P ig Atr ia . Isolated guinea
pig left atria (from 300 to 500 g male animals) were placed in
20 mL organ baths containing a solution of the following
composition (mM): NaCl 131.6, KCl 5.6, CaCl2 1.8, NaH2PO4
1.036, NaHCO3 24.99, glucose 11, sucrose 13; under 500 mg
resting tension, at 32 °C. The solution was continuously
bubbled with a mixture of 95% O2 and 5% CO2. The prepara-
tions were stimulated by platinum electrodes by square-wave
pulses at a frequency of 1 Hz (1 ms duration, voltage twice
the treshold). After a 60 min equilibration period, cumulative
concentrations of the compounds were added, each concentra-
tion being left in contact until the maximal response or
arrhythmias were observed.
1
3a-ol (0.68 g, 58%) as a white foam. H NMR (CDCl3) δ 0.95
(s, 3H, CH3), 2.08 (s, 3H, OAc), 3.98 (m, 1H, CHOH), 4.06 (dd,
1H, CHHOAc), 4.22 (dd, 1H, CHHOAc). 13C NMR (CDCl3) δ
14.4 (q), 21.1 (q), 23.9 (t), 24.1 (t), 24.3 (t), 25.2 (t), 32.6 (t),
32.7 (t), 35.8 (t), 36.9 (t), 39.5 (d), 39.9 (t), 41.8 (d), 46.2 (s),
48.1 (d), 66.7 (d), 67.8 (t), 82.9 (s), 170.9 (s).
To a solution of the above-described alcohol (0.68 g, 2.0
mmol) in THF (20 mL) was added IBX (0.704 g, 2.5 mmol),
and the mixture was heated at reflux for 1 h. The reaction
mixture was cooled to room temperature and filtered on a
Celite pad. The organic solvent was evaporated to dryness to
1
Refer en ces
give 112 (0.68 g, 100%) as a glassy solid. H NMR (CDCl3) δ
0.98 (s, 3H, CH3), 2.08 (s, 3H, OAc), 4.08 (dd, 1H, CHHOAc),
4.22 (dd, 1H, CHHOAc).
(1) Hoffmann, B. F.; Bigger, J . T., J r. Digitalis and Allied Cardiac
Glycosides. In The Pharmacological Basis of Therapeutics, 8th
ed.; Gilman, A. G., Rall, T. W., Nies, A. S., Taylor, P., Eds.;
Pergamon Press: New York, 1990; pp 814-839.
(2) Repke, K. R. H.; Sweadner, K. J .; Weiland, J .; Megges, R.; Scho¨n,
R. In Search of Ideal Inotropic Steroids: Recent Progress. Prog.
Drug Res. 1996, 47, 9-52.
(3) Quadri, L.; Cerri, A.; Ferrari, P.; Folpini, E.; Mabilia, M.; Melloni,
P. Synthesis and Quantitative Structure-Activity Relationships
of 17â-Hydrazonomethyl-5â-androstane-3â,14â-diol Derivatives
That Bind to Na+,K+-ATPase Receptor. J . Med. Chem. 1996, 39,
3385-3393.
(4) Cerri, A.; Serra, F.; Ferrari, P.; Folpini, E.; Padoani, G.; Melloni,
P. Synthesis, Cardiotonic Activity, and Structure-Activity
Relationships of 17â-Guanylhydrazone Derivatives of 5â-An-
drostane-3â,14â-diol Acting on the Na+,K+-ATPase Receptor. J .
Med. Chem. 1997, 40, 3484-3488.
(5) De Munari, S.; Barassi, P.; Cerri, A.; Fedrizzi, G.; Gobbini, M.;
Mabilia, M.; Melloni, P. A New Approach to the Design of Novel
Inhibitors of Na+,K+-ATPase: 17R-Substituted Seco-D 5â-
Androstane as Cassaine Analogues. J . Med. Chem. 1998, 41,
3033-3040.
(6) Prigent, A. F.; Grouiller, A.; Pacheco, H. Synthetic Compounds
Related to Cardenolides. III. Pharmacological and Biochemical
Studies of New Cardenolides Analogs. Chim. Ther. 1972, 7, 329-
336.
(1S,3a S,5S,7a R)-1-Acetoxym eth yl-5-(4-tr a n s-h yd r oxy-
1-cycloh exyl)-7a -m eth ylp er h yd r oin d en e-3a -ol (113). To
a solution of 112 (0.68 g, 2.0 mmol) in THF (40 mL) maintained
at -78 °C, under nitrogen was dropped a solution of LiAlH-
(OtBut)3 (1.08 g, 4.0 mmol) in THF (40 mL). After the mixture
was stirred for 3 h at -78 °C, a solution of LiAlH(OtBut)3 (0.54
g, 2.0 mmol) in THF (20 mL) was added, and the mixture was
allowed to warm to room temperature over 1 h. Acetic acid
was added (2.16 mL), and the mixture was diluted with brine
and extracted with EtOAc. The organic phase was dried over
Na2SO4 and evaporated to dryness to give 113 (0.68 g, 100%)
as a glassy oil, containing 10% of the isomer cis-alcohol. 1H
NMR (CDCl3) δ 0.95 (s, 3H, CH3), 2.08 (s, 3H, OAc), 3.54 (m,
1H, W1/2h ) 21 Hz, CHOH), 4.07 (dd, 1H, CHHOAc), 4.22 (dd,
1H, CHHOAc). 13C NMR (CDCl3) δ 14.4 (q), 21.1 (q), 24.3 (t),
25.3 (t), 28.2 (t), 28.3 (t), 35.7 (t), 35.7 (t), 35.7 (t), 36.9 (t),
39.9 (t), 40.1 (d), 41.8 (d), 46.2 (s), 48.0 (d), 66.7 (t), 71.2 (d),
82.9 (s), 170.9 (t).
(1S,3a S,5S,7a R)-1-Acetoxym eth yl-5-(4-tr a n s-ter t-bu tyl-
dim eth ylsilyloxy-1-cycloh exyl)-7a-m eth ylper h ydr oin den e-
3a -ol (114). To a solution of 113 (0.68 g, 2.0 mmol) in DMF (8
mL) were added imidazole (0.64 g, 8.0 mmol) and tert-
butyldimethylsilyl chloride (0.56 g, 3.0 mmol). After being
stirred for 3 h, the mixture was diluted with 5% aqueous
NaHCO3 and extracted with EtOAc. The organic phase was
dried over Na2SO4 and evaporated to dryness to give 114. The
crude product, containing tert-butyldimethylsilanol, was used
directly in the next step without further purification.
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(1S,3a S,5S,7a R)-5-(4-tr a n s-ter t-Bu tyld im eth ylsilyloxy-
1-cycloh exyl)-3a -h yd r oxy-7a -m et h ylp er h yd r oin d en e-1-
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J M011001K