Synthesis and biological activity of allosteric modulators of GABA B receptors, Part 2. 3-(2,6-Bis-tert-butyl-4-hydroxyphenyl)propanols

Article abstract of DOI:10.1071/CH06164

A series of 13 2,2-disubstituted 3-(3,5-di-t-butyl-4-hydroxyphenyl)propan- 1-ol derivatives have been prepared for evaluation as allosteric modulators of GABA_B receptors. The activity (EC₅₀, 4?7 ?M) was greatest for the cyclohexyl and cyclopentyl analogues. CSIRO 2006.

Full text of DOI:10.1071/CH06164

Full Paper
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2006, 59, 457–462
Synthesis and Biological Activity of Allosteric Modulators of GABAB
Receptors, Part 2. 3-(2,6-Bis-tert-butyl-4-hydroxyphenyl)propanols∗
David I. B. Kerr,A,D Jabbar Khalafy,B,C Jennifer Ong,A Michael V. Perkins,B
Rolf H. Prager,B,E Ni Made Puspawati,B and Mehdi RimazC
A Department of Anaesthesia and Intensive Care, University of Adelaide, Adelaide SA 5005, Australia.
B School of Chemistry, Physics and Earth Sciences, Flinders University, Adelaide SA 5001, Australia.
C Chemistry Department, Urmia University, Urmia 57154, Iran.
D Deceased, July 2005.
E Corresponding author. Email: rolf.prager@flinders.edu.au
A series of 13 2,2-disubstituted 3-(3,5-di-t-butyl-4-hydroxyphenyl)propan-1-ol derivatives have been prepared for
evaluationasallostericmodulatorsofGABAB receptors.Theactivity(EC50, 4–7 µM)wasgreatestforthecyclohexyl
and cyclopentyl analogues.
Manuscript received: 16 May 2006.
Final version: 5 July 2006.
R1
But
Introduction
HO
R1
HO
But
R2 R3
CHO
Aseriesofcompoundswithgeneralformula 1(Fig. 1), 3-(3,5-
di-tert-alkyl-4-hydroxyphenyl)-2,2-di-substituted propanals,
areknowntostabilizeorganicmaterialsnormallysubjectedto
deterioration caused by heat, light, and oxygen. In addition to
beingantioxidants, theyareevenmoreusefulasintermediates
for the preparation of high molecular weight antioxidants for
polypropylene and other polymers.[1]
R
1
2 R ϭ CHO
3 R ϭ CH2OH
Fig. 1.
Following a random mass screening, Urwyler et al.[2]
recentlyreportedthat2,6-di-tert-butyl-4-(3-hydroxyphenyl)-
2,2-dimethylpropionaldehyde, CGP 13501, 2 acted as a
positive allosteric modulator for GABAB receptors,[3,4] and
its reduction product, the corresponding alcohol CGP 7930
3 was found to be even more potent. γ-Aminobutyric
acid (GABA) is one of the major inhibitory neurotrans-
mitters which regulates synaptic transmission and neuronal
excitability in the mammalian central and peripheral ner-
vous systems.[5–7] Defects in GABA-ergic transmission
can cause a variety of neurological and psychiatric dis-
eases such as spasticity,[8] epilepsy,[9] and Huntington’s[10]
and Parkinson’s[11] diseases. GABAB receptors are also
implicated in drug addiction related to alcohol[12,13] and
cocaine.[14]
HO
HO
CO2H
4
5
Fig. 2.
bolus injections or by continuous infusion. GHB is best
known as a drug of abuse,[19] and is a GABA analogue.
Our working hypothesis for the lead compound 3 is that
it acts through the 3-hydroxyphenylpropyl moiety, with the
hydroxyphenyl group mimicking the carboxyl group of GHB,
in addition to providing hydrophobic properties that would
facilitate transport across cell membranes.
Despite the relatively high activity of 3, little is known of
the pharmacokinetics of CGP 7930, and its therapeutic poten-
tial is uncertain. This present work therefore initially aimed
to prepare a new series of analogues 6 in order to explore
the changes in modulatory activity at GABAB receptors. The
synthetic approach to prepare compounds 6 is basically that
of Urwyler et al.[2] (Scheme 1).
Because of our interest in such modulators,[3,15,16] we
speculated that the latter could be regarded as a hybrid of
propofol 4 and γ-hydroxybutyric acid (GHB, 5; Fig. 2).
Propofol[17,18] is a short-acting hypnotic agent (GABAA
modulator), effectiveforinductionandmaintenanceofanaes-
thesia when administered intravenously either as repeated
∗
Part 1: D. I. B. Kerr, J. Ong, M. V. Perkins, R. H. Prager, N. M. Puspawati, Aust. J. Chem. 2006, 59, 445. doi:10.1071/CH06163
© CSIRO 2006 10.1071/CH06164
0004-9425/06/070457

458
D. I. B. Kerr et al.
R1
R2
R3
But
But
But
HO
But
HO
But
HO
But
O
R1 R2
CH2O, KOH, MeOH
95%
R3
R4
KOH, 65°C
53–92%
OMe
O
7
NaBH4
R1
Me
-(CH2)4-
-(CH2)5-
Me Me
Me
Me
Ph
R2
Me
74–97%
But
8a
8b
8c
8d
8e
8f
H
H
H
Me
Me
HO
But
R1 R2
R3
H
H
Me
H
OH
4-ClPh
Ph
R1
R2
Me
R4
8g
Me
H
H
H
6a
6b
6c
-(CH ) -
-(CH22)45-
6d
6e
6f
6g
6h
6i
Me
Me
Me
Me
CH=CHMe H
-(CH2)5-
H
Me
4-ClPh
Ph
Me
Me
Ph
H
H
Me
Scheme 1.
But
But
But
HO
HO
But
HO
But
CH3CH2CHO
But
OMe
CHO
CHO
OH
7
9
But
But
But
OH
HO
But
HO
But
HO
But
CHO
CHO
CHO
11
10
Scheme 2.
Me
Discussion
HO
R
CH
2,6-Di-t-butyl-4-methoxymethylphenol 7[20] was reacted
withanumberofaldehydesandketones, thealdehydesrequir-
ing 3 h at 65◦C, the ketones 20 h at 65◦C for completion,
affording 8 in moderate to good yield.
CH
H
ϪOH
11
9
O
CH
Me
12
OH
When the aldehyde used was propanal, a 2:1 addition–
elimination product 9 was isolated. 1H NMR analysis showed
the structure to be 9 rather than the more expected 10. The
1H NMR spectrum showed two vinyl protons resonating at
δH 5.47 and 5.49 and only one methyl group besides those of
the t-butyl groups. The proposed scheme for the formation of
9 is shown in Scheme 2. The elimination of water from the
initially formed 2:1 adduct 11 under basic conditions is note-
worthy, and may be due to the formation of a cyclic transition
state, after addition of base to the aldehyde group (Scheme
3, structure 12).
Scheme 3.
enhancing baclofen-induced hyperpolarizing responses at
GABAB post-synaptic receptors.[23,24] Baclofen is a classi-
cal selective agonist at GABAB receptor sites,[25,26] and is
commonly used in rat brain preparations to stimulate these
receptors to induce a neuronal response. Herein we sum-
marize the results of the effects of the test compounds in
modulating baclofen mediated function using grease gap
recording in rat neocortical slices.[21,22]
Our results on the potentiating effects of the test com-
pounds on baclofen-induced hyperpolarizing responses in rat
brain slices are summarized in Table 1 below. The responses
induced by baclofen are dose-dependent, with baclofen gen-
erating an EC50 value of approximately 10 µM.[21] The
potencies of the various compounds are measured as their
respective EC50 values where the EC50 is defined as the
concentration of the drug giving a response equal to 50%
of the maximally effective concentration in potentiating the
baclofen response.
The carbonyl group in 8 was subsequently reduced to alco-
hol 6 with sodium borohydride. It can be also reacted with a
Grignard reagent or alkyl lithium to give a higher alcohol (e.g.
8c to 6f), but when it became clear that considerable reduc-
tion in activity occurs with bulkier groups adjacent to the
alcohol, this approach was not pursued further. Before this,
we used the same general approach to prepare the ketones 8f,
13, 8g, 15, 17, and 19 (Fig. 3), and converted them into their
corresponding alcohols for biological evaluation.
Asdescribedpreviously,[15,21,22] thecompoundsdescribed
above were examined for their pharmacological effects in

Synthesis and Biological Activity of Allosteric Modulators of GABAB Receptors
459
But
HO
But
X,Y
13 XϭYϭO
14 XϭH, YϭOH
But
OH
But
But
But
X
HO
But
HO
But
X,Y
X,Y
But
But
15 XϭYϭO
16 XϭH, YϭOH
17 XϭYϭO
Cl
18 XϭH, YϭOH
HO
HO
But
But
19 XϭYϭO
20 XϭH, YϭOH
But
But
OH
Fig. 3.
Table 1. Pharmacological activity (EC50
)
of
3-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-
3-(4-hydroxyaryl)propanols as GABAB potentiators
All numerical data on the concentration-response
curves were expressed as approximate EC50
values (n = 6–12)
2,2-dimethylpropanol 6a
A
mixture of 3-(3,5-di-t-butyl-4-hydroxyphenyl)-2,2-dimethyl-
propanal[1] (1.0 g, 3.5 mmol), andsodiumborohydride(0.15 g, 3.5 mmol)
in ethanol (10 mL) was refluxed overnight. Water was added to the mix-
ture, which was then extracted with ether. The ether extract was washed
with brine, dried over Na2SO4 and concentrated to yield a yellow solid
which was recrystallized from hexane to afford 6a as a pale yellow
solid (0.98 g, 97%), mp 80–82◦C. (Found: [M + H − H2O]+ 275.2365.
C19H31O requires 275.2375). δH 0.92 (s, 6H), 1.49 (s, 18H), 2.54 (s,
2H), 3.37 (s, 2H), 5.14 (s, 1H, OH), 6.99 (s, 2H). δC 23.9 (2 × CH3),
30.4 (6 × CH3), 34.1 (CH2), 36.4 (C), 44.8 (C), 71.5 (CH2), 126.8 (CH),
129.2 (C), 135.2 (C), 151.9 (C).
Compound
Activity
6a
6b
6c
6d
6e
6f
6g
6h
6i
10 µM
50 µM
30 µM
7 µM
50 µM
>50 µM
10 µM
50 µM
1-[{3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl}methyl]-
1-hydroxymethylcyclopentane 6b
50 µM
14
16
18
20
30 µM
1-[{3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl}methyl]-
cyclopentanecarboxaldehyde 8b
100 µM
InactiveA
InactiveA
A solution of 2,6-(di-t-butyl-4-methoxymethyl)phenol 7[20] (2.0 g,
8 mmol) and potassium hydroxide (0.08 g) in methanol (8 mL) was
heated to 60◦C. Cyclopentanecarboxaldehyde (0.9 g, 9 mmol) was
added to the solution over 10 min and the reaction mixture was refluxed
for 3 h. The cooled reaction mixture was poured into 1% acetic acid
(12.5 mL) and the product was subjected to flash silica gel column chro-
matography using hexane/dichloromethane as eluent.The major product
8b was recrystallized from hexane as pale yellow crystals (1.52 g, 61%),
mp 54–56◦C. (Found: [M + H]+ 317.2490. C21H33O2 requires M+
317.2481). δH 1.45 (s, 18H), 1.63 (m, 4H), 1.93 (m, 4H), 2.85 (s, 2H),
5.01 (s, 1H, OH), 6.89 (s, 2H), 9.57 (1H). δC 27 (2 × CH2), 30.3 (6 ×
CH3), 32.2 (2 × CH2), 34.2 (CH2), 41.3 (2 × C), 59.3 (C), 126.3 (CH),
128.3 (C), 135.5 (C), 152.3 (C), 205.6 (CH).
A mixture of 8b (1 g, 3 mmol) and sodium borohydride (0.13 g,
3.4 mmol) in ethanol (10 mL) was reacted as for 6a. The solid 6b was
recrystallized from hexane as colourless crystals (0.89, 79%) mp 88–
89◦C. (Found: [M + H − H2O]+ 301.2528. C21H33O requires [M+]
301.2526). δH 1.43 (s, 18H), 1.45 (m, 2H), 1.63 (m, 6H), 2.61 (s, 2H),
3.45 (s, 2H), 6.99 (s, 2H). δC 24.5 (CH2), 29.4 (CH2), 30.4 (6 × CH3),
32.3 (CH2), 34.1 (2 × C), 34.2 (CH2), 42.7 (C), 68.1 (CH2), 126.7 (CH),
129.2 (C), 141.7 (C), 152.0 (C).
A
Essentially insoluble in test procedure.
All the 3-(hydroxyphenyl)propanol derivatives had sim-
ilar activity with EC50 typically around 10 µM (Table 1).
The 2-aryl and highly substituted analogues showed only low
activity, but this may be a reflection of their extremely low
solubility even in DMSO/water mixtures. The general activ-
ity was several orders of magnitude lower than that of the
N-(phenylpropyl)-1-arylethylamines.[3] There is clearly a
need to find more water-soluble derivatives.
Conclusions
Generally, it can be concluded that 3-(4-hydroxy-3,5-di-
tert-butylphenyl)propanols represent a new distinct class of
moderately active GABAB receptor modulators, limited at
this stage by very poor solubility. However, these GABAB
modulators may still represent a novel therapeutic strategy
for the treatment of various neurological and pathological
diseases mentioned previously without the side effects of full
GABAB receptor agonists.
1-[{3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl}methyl]-
1-hydroxymethylcyclohexane 6c
Amixtureof1-[{3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl}methyl]-
cyclohexanecarboxaldehyde 8c[1] (0.67 g, 2 mmol) and sodium borohy-
dride (0.1 g, 2 mmol) in ethanol (10 mL) was reacted as above. The solid
6c was recrystallized from hexane as colourless crystals (0.52 g, 79%),
mp 88–90◦C. (Found: [M + H − H2O]+ 315.2065. C22H35O requires
315.2082). δH 1.31 (m, 6H), 1.42 (s, 18H), 1.45 (m, 4H), 2.62 (s, 2H),
Experimental
General experimental conditions have been detailed in Part 1.[3]

460
D. I. B. Kerr et al.
3.40 (s, 2H), 7.03 (s, 2H). δC 21.6 (CH2), 26.4 (CH2), 30.4 (6 × CH3),
32.3 (CH2), 34.1 (2 × C), 38.4 (CH2), 41.8 (C), 67.7 (CH2), 126.7 (CH),
129.1 (C), 135.3 (C), 152.3 (C).
using hexane/dichloromethane (1/1) as eluent to give 8e as a white solid
(0.76 g, 66%), mp 90–91◦C. (Found: [M + H]+ 291.2341. C19H31O2
requires [M+] 291.2324). δH 1.12 (d, J 6.9, 3H), 1.45 (s, 18H), 2.14 (s,
3H), 2.51 (dd, J 13.4, 7.2, 1H), 2.81 (sext, J 6.9, 1H), 2.94 (dd, J 13.4,
7.2, 1H), 5.1 (s, 1H), 6.95 (s, 2H). δC 16.30, 28.85, 30.35, 34.28, 39.06,
49.13, 125.36, 130.13, 135.82, 152.15, 212.74. νmax (KBr)/cm−1 3560,
3008, 2963, 2872, 1708, 1585, 1434, 1359, 1302, 1237, 1214, 1121,
1097, 878, 774.
A mixture of 8e above (300 mg) and sodium borohydride (90 mg)
in dry ethanol (10 mL) was reacted as above to give essentially a
1:1 mixture of diastereoisomers of 6g as a pale yellow viscous oil
(240 mg, 80%). (Found: [M − OH]+ 275.2365. C19H31O requires [M+]
275.2375). δH 0.89 (d, J 7.2, 3H in one isomer), 0.93 (d, J 7.2, 3H in
other isomer), 7.06 (s, 2H in one isomer), 7.01 (s, 2H in other isomer),
1.32–1.21 (m, 4H), 1.5 (s, 18H), 2.35 (dd, J 13.5, 7.5, 1H), 2.79 (dd,
J 13.5, 7.8, 1H), 3.75–3.87 (m, 1H in both isomers), 5.11 (s, 1H). δC
13.7, 14.6, 19.4, 20.5, 30.4, 34.3, 39.3, 41.8, 42.4, 70.6, 71.5, 125.5,
131.5, 135.7, 151.8. νmax(KBr)/cm−1 3647, 3414, 2962, 2869, 1435,
1362, 1316, 1234, 1157, 1121, 928, 889, 787, 769.
4-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-3,3-dimethyl-
2-butanol 6d
A
mixture of 4-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-3,3-
dimethyl-2-butanone 8d[1] (0.80 g, 2.6 mmol) and sodium borohydride
(0.13 g, 3.4 mmol) in ethanol (10 mL) was reacted as above to yield
6d, which was recrystallized from hexane as colourless crystals (0.79 g,
78%), mp 72–74◦C. (Found: [M + H − H2O]+ 289.2535). C20H33
O
requires [M+] 289.2526). δH 0.83 (s, 3H), 0.88 (s, 3H), 1.21 (d, J 6.4,
3H), 1.46 (s, 18H), 2.47 (d, J 13.4, 1H), 2.54 (d, J 13.2, 1H), 3.58 (q,
J 6.4, 1H), 6.98 (s, 2H). δC 17.9 (CH3), 21.7 (CH3), 23.0 (CH3), 30.4
(6 × CH3), 34.1 (2 × C), 38.6 (CH2), 45.0 (C), 70.0 (CH), 127.1 (CH),
129.2 (C), 135.0 (C), 152.9 (C).
3-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2-methyl-
2-(prop-1-enyl)propanol 6e
3-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2-methyl-
2-(1-prop-1-enyl)propanal 9
3-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-
1-(-4-chlorophenyl)-2-methyl-1-propanol 6h
A solution of 7 (2.0 g, 8 mmol) and potassium hydroxide (0.08 g)
in methanol (8 mL) was heated to 60◦C. Propanal (0.56 g, 8 mmol)
was added to the solution over 10 min and the reaction mixture was
treated as for 8b. Flash silica gel column chromatography using
hexane/dichloromethane as eluent gave a yellow solid which was recrys-
tallizedfromhexanetoyield 9asawhitesolid(0.79, 45%), mp60–62◦C.
(Found: [M + H]+ 317.2470. C21H33O2 requires [M+] 317.2481). δH
1.09 (s, 3H), 1.42 (s, 18H), 1.75 (d, J 4.6, 3H), 2.80 (d, J 13.6, 1H),
2.83 (d, J 13.6, 1H), 5.47 (dd, J 4.6, 3.6, 1H), 5.49 (d, J 3.6, 1H), 5.09
(s, 1H, OH), 6.89 (s, 2H), 9.50 (1H). δC 18.3 (CH3), 20.5 (CH3), 30.3
(6 × CH3), 34.1 (C), 42.2 (C), 43.2 (CH2), 43.9 (CH2), 124.6 (CH),
126.9 (CH), 128.3 (C), 134.9 (C), 136.7 (C), 151.9 (C), 189.1 (CH).
A mixture of 9 (0.4 g, 1 mmol) and sodium borohydride (0.1 g,
1 mmol) in ethanol (10 mL) was reacted as above to yield 6e as a pale
3-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-
1-(-4-chlorophenyl)-2-methyl-propan-1-one 8f
4-Chlorophenylpropan-1-one (0.668 g, 4 mmol) was added over
10 min to a solution of 7 (1 g, 4 mmol) and potassium hydroxide (0.04 g)
in methanol (4 mL) at 60◦C. After 3 h the reaction was worked up as
above and the product was subjected to flash silica gel column chro-
matography using hexane/dichloromethane (1/1) as eluent to give 8f as
a white solid (1.2 g, 77%), mp 73–75◦C. (Found: [M + H]+ 387.2088.
C24H3235ClO2 requires [M+] 387.2091). δH 1.27 (d, J 6.85, 3H), 1.41
(s, 18H), 2.72 (dd, J 13.8, 6.85, 1H), 3.04 (dd, J 13.8, 7.3, 1H), 3.69
(sep, J 6.85, 1H), 5.07 (s, 1H), 6.94 (s, 1H), 7.40 (d, J 8.6, 2H), 7.79 (d,
J 8.6, 2H). δC 18.0, 30.6, 34.6, 40.6, 43.4, 125.8, 129.1, 130.1, 130.5,
135.6, 136.1, 139.5, 152.5, 203.8. νmax(KBr)/cm−1 3570, 3065, 3020,
2959, 2921, 2878, 1683, 1590, 1434, 1401, 1358, 1310, 1240, 1216,
1134, 1092, 976, 841, 756, 637.
A mixture of 8f (280 mg) and sodium borohydride (75 mg) in dry
ethanol (10 mL) was reacted as above to give a diastereoisomeric mix-
ture of 6h as a pale yellow oil (246 mg, 87%). (Found: [M − OH]+
371.2160. C24H32ClO requires [M+] 371.2142). δH 0.73 (d, J 6.6, 3H
in one isomer), 0.89 (d, J 6.6, 3H in other isomer), 1.48 (s, 18H), 2.02–
2.16 (m, 1H), 2.29–2.42 (m, 1H in both isomers), 2.73 (dd, J 13.5, 6.3,
1H in one isomer), 2.94 (dd, J 13.5, 4.2, 1H in other isomer), 4.52 (d,
J 6.9, 1H in one isomer), 4.64 (d, J 4.5, 1H in other isomer), 5.1 (s,
1H), 6.98 (s, 2H in one isomer), 6.99 (s, 2H in other isomer), 7.32 (d, J
8.7, 2H), 7.36 (d, J 8.7, 2H). δC 13.6, 15.6, 30.3, 34.2, 38.8, 39.5, 42.2,
76.1, 76.6, 78.1, 125.7, 127.6, 128.2, 128.3, 128.4, 130.9, 131.0, 132.7,
133.1, 135.7, 135.8, 141.7, 142.3, 151.9. νmax(KBr)/cm−1 3642, 3422,
2960, 2925, 2875, 1598, 1490, 1435, 1390, 1325, 1325, 1234, 1213,
1156, 1120, 1090, 1013, 931, 886, 823, 799, 769, 723, 655.
yellow oil (0.40 g, 74%). (Found: [M + H − H2O]+ 301.2532. C21H33
O
requires [M+] 301.2526). δH 0.94 (s, 3H), 1.44 (s, 18H), 1.73 (d, J 4.6,
3H), 2.55 (s, 2H), 3.35 (d, J 13.6, 1H), 3.40 (d, J 13.6, 1H), 5.30 (s,
1H, OH), 5.41 (dq, J 4.8, 4.6, 1H), 5.43 (d, J 4.8, 1H), 6.93 (s, 2H). δC
13.4 (CH3), 20.6 (CH3), 30.3 (6 × CH3), 34.1 (C), 42.4 (C), 43.9 (CH2),
69.6 (CH2), 124.9 (CH), 127.0 (C), 128.4 (CH), 136.8 (C), 139.0 (C),
151.9 (C).
1-[{3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl}methyl]-
1-(1-hydroxyethyl) Cyclohexane 6f
To a solution of 8c (0.33 g, 1 mmol) in dry ether (10 mL) at 0◦C was
added dropwise 1.5 M methyllithium (0.10 mL). The reaction mixture
was stirred at room temperature for 20 min. Water was added and
the mixtures were extracted with ether. The combined extracts were
dried over MgSO4, concentrated, and the solid was recrystallized from
hexane to afford 6f as white crystals (0.31 g), mp 95–96◦C. (Found:
[M + H − H2O]+ 329.2837. C23H37O requires [M+] 329.2839). δH
1.21 (d, J 6.4, 3H), 1.37 (m, 6H), 1.42 (s, 18H), 1.56 (m, 4H), 2.61
(d, J 13.6, 1H), 2.72 (d, J 13.6, 1H), 3.68 (q, J 6.4, 1H), 5.05 (1H,
OH), 7.03 (s, 2H). δC 17.3 (CH3), 21.5 (2 × CH2), 26.3 (CH2), 30.4
(6 × CH3), 30.7 (CH2), 34.2 (2 × C), 37.9 (CH2), 40.1 (C), 71.3 (CH2),
127.1 (CH), 129.4 (C), 135.3 (C), 151.9 (C).
2-[{3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl}methyl]-
2-methyl-1-cyclohexanol 14
2-[{3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl}methyl]-
2-methylcyclohexanone 13
2-Methylcyclohexanone (0.448 g) was reacted with a mixture of 7
(1 g, 4 mmol) and potassium hydroxide (0.04 g) in methanol (4 mL) at
60◦C as above.After 4 h the product was subjected to flash silica gel col-
umn chromatography using hexane/dichloromethane (1/1) as eluent to
give 13 as a yellow solid (0.93 g, 70%), mp 61–63◦C. (Found: [M + H]+
331.2645. C22H35O2 requires [M+] 331.2637). δH 1.02 (s, 3H), 1.44 (s,
18H), 1.76–1.91 (m, 6H), 2.53 (t, J 6.9, 2H), 2.82 (s, 2H), 5.1 (s, 1H),
6.9 (s, 2H). δC 21.1, 22.6, 27.4, 30.3, 34.2, 38.0, 38.9, 42.9, 49.4, 126.9,
127.8, 135.2, 152.2, 215.8. νmax(KBr)/cm−1 3590, 2952, 2885, 1698,
1436, 1390, 1360, 1311, 1236, 1215, 1158, 1121, 926, 881, 769, 620.
4-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-
3-methyl-2-butanol 6g
4-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-
3-methyl-2-butanone 8e
Butan-2-one (0.288 g) was added to a solution of 7 (1 g, 4 mmol)
and potassium hydroxide (0.04 g) in methanol (4 mL) at 60◦C over
10 min, and the reaction mixture was refluxed for 4 h. The cooled
mixture was poured into 1% acetic acid (8 mL) to yield a thick yel-
low oil which was subjected to flash silica gel column chromatography

Synthesis and Biological Activity of Allosteric Modulators of GABAB Receptors
461
A mixture of 13 (150 mg) and sodium borohydride (45 mg) in dry
ethanol (5 mL) was reacted as above, to yield 14 as a yellow crystalline
mixture of diastereoisomers (120 mg, 80%), mp 51–53◦C. (Found:
[M − OH]+ 315.2696. C22H35O requires [M+] 315.2688). δH 0.88
(s, 3H in one isomer), 0.92 (s, 3H in other isomer), 1.45 (s, 18H in
one isomer), 1.46 (s, 18H in other isomer), 1.50–1.78 (m, 8H), 2.60 (dd,
J 13.5, 8.4, 1H in one isomer), 2.65 (dd, J 13.5, 6.9, 1H in other isomer),
3.42 (dd, J 7.2, 4.5, 1H in one isomer), 3.47 (dd, J 8.1, 3.3, 1H in other
isomer), 5.05 (br s, 1H), 6.98 (s, 2H in one isomer), 6.99 (s, 2H in other
isomer). δC 16.7, 21.2, 21.4, 23.2, 24.1, 24.5, 29.7, 29.9, 30.4, 30.7, 33.7,
34.2, 35.6, 38.7, 39.3, 47.3, 75.4, 76.6, 127.1, 127.2, 129.0, 129.2, 135.0,
135.1, 151.8. νmax(KBr)/cm−1 3646, 3437, 2960, 2955, 2867, 1436,
1391, 1361, 1317, 1234, 1214, 1159, 1121, 1045, 902, 882, 769, 618.
2,2-Bis[{3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl}methyl]-
1,2,3,4-tetrahydronaphthalen-1-ol 18
2,2-Bis[{3,5-bis(1,1-dimethylethyl)-
4-hydroxyphenyl}methyl]-1-tetralone 17
1-Tetralone (0.292 g, 2 mmol) was added to a mixture of 7 (1 g,
4 mmol) and potassium hydroxide (0.04 g) in methanol (4 mL) at 60◦C
as above. The product was subjected to flash silica gel column chro-
matography using hexane/dichloromethane (1/1) as eluent to give 17 as a
white solid (0.72 g, 62%) mp 140–142◦C. (Found: [M + H]+ 583.4170.
C40H55O3 requires [M+] 583.4151). δH 1.42 (s, 36H), 1.96 (t, J 6,
2H), 2.61 (d, J 13.5, 2H), 2.92 (t, J 6, 2H), 3.31 (d, J 13.5, 2H), 5.08
(s, 2H), 6.97 (s, 4H), 7.16 (d, J 7.5, 1H), 7.30 (t, J 7.8, 1H), 7.43 (t,
J 7.2, 1H), 8.09 (d, J 7.8, 1H). δC 14.1, 22.6, 25.4, 28.7, 30.3, 31.6,
34.2, 42.6, 51.1, 126.4, 127.4, 127.7, 128.1, 128.5, 132.8, 133.1, 135.2,
143.3, 152.2, 201.9. νmax(KBr)/cm−1 3636, 3567, 3020, 2955, 2920,
2872, 1678, 1602, 1434, 1389, 1358, 1235, 1120, 926, 743.
3-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-
1,2-diphenylpropan-1-ol 6i
A mixture of 17 (160 mg) and sodium borohydride (63 mg) in dry
ethanol (5 mL) and THF (2 mL) was reacted as above to give 18 as a
whitesolid(140 mg, 87%), mp88–90◦C. (Found:[M − OH]+ 567.4225.
C40H55O2 requires [M+] 567.4202). δH 1.42 (s, 9H), 1.45 (s, 18H), 1.47
(s, 9H), 2.47 (d, J 13.5, 1H), 2.63 (t, J 13.5, 1H), 2.85 (d, J 13.8, 2H), 3.11
(d, J 13.5, 1H), 3.31 (d, J 13.5, 1H), 5.14 (br s, 1H), 4.47 (s, 1H), 6.97 (s,
2H), 7.04 (s, 1H), 7.06 (s, 2H), 7.15–7.27 (m, 3H), 7.56 (br d, J 6, 1H).
δC 25.7, 28.0, 30.3, 30.4, 34.2, 34.3, 37.4, 41.5, 42.6, 51.1, 53.4, 72.8,
126.0, 126.4, 126.7, 126.9, 127.3, 127.4, 127.7, 128.1, 128.5, 128.6,
129.0, 135.2, 135.3, 135.5, 139.5, 152.1, 152.2. νmax(KBr)/cm−1 3642,
3504, 3425, 2957, 2920, 2872, 1602, 1435, 1361, 1236, 1156, 1121,
910, 734.
3-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-
1,2-diphenylpropan-1-one 8g
Deoxybenzoin (0.785 g, 4 mmol) was added to a mixture of 7 (1 g,
4 mmol) and potassium hydroxide (0.04 g) in methanol (4 mL) at 60◦C
as above. The product was subjected to flash silica gel column chro-
matography using hexane/dichloromethane (1/1) as eluent to give 8g
as yellow crystals (1.33 g, 80%), mp 103–104◦C. (Found: [M + H]+
415.2647. C29H35O2 requires [M+] 415.2637). δH 1.38 (s, 18H), 3.08
(dd, J 13.8, 7.2, 1H), 3.5 (dd, J 13.8, 7.2, 1H), 4.77 (t, J 7.3, 1H), 5.1 (s,
1H), 6.81 (s, 2H), 7.23–7.51 (m, 8H), 7.96 (d, J 7.2, 2H). δC 30.2, 30.3,
34.2, 40.2, 55.1, 125.6, 127.0, 128.4, 128.5, 128.7, 128.7, 130.1, 132.7,
135.5, 137.0, 139.4, 152.0, 199.9. νmax(KBr)/cm−1 3627, 3020, 2963,
2923, 2878, 1669, 1599, 1581, 1434, 1390, 1357, 1324, 1262, 1234,
1212, 1170, 1122, 980, 852, 756, 700, 670.
A mixture of 8g (420 mg) and sodium borohydride (120 mg) in dry
ethanol (10 mL) was reacted as above to give 6i as a white solid (350 mg,
83%), mp 94–96◦C. (Found: [M − OH]+ 399.2700. C29H35O requires
[M+] 399.2688). δH 1.36 (s, 18H), 2.80 (d, J 7.5, 2H), 3.15 (dd, J 7.8,
7.5, 1H), 4.91 (d, J 7.8, 1H), 4.95 (s, 1H), 6.62 (s, 2H), 7.15 (d, J 7.2,
2H), 7.19–7.39 (m, 8H). δC 30.2, 34.1, 38.5, 56.1, 125.4, 126.7, 126.9,
128.7, 128.2, 129.2, 135.2, 140.7, 142.7, 151.7. νmax(KBr)/cm−1 3641,
3436, 3063, 3028, 2956, 2898, 2870, 1603, 1452, 1435, 1391, 1315,
1234, 1152, 1025, 878, 759, 701.
2,2-Bis[{3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl}methyl]-
1-(4-chlorophenyl)-propan-1-ol 20
2,2-Bis[{3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl}methyl]-
1-(4-chlorophenyl)propan-1-one 19
Ketone 8f was added to a mixture of 7 (0.25 g, 1 mmol) and
potassium hydroxide (0.02 g) in methanol (2 mL) at 60◦C as above.
The product was subjected to flash silica gel column chromatography
using hexane/dichloromethane (1/1) as eluent to give 19 as a white
solid (0.37 g, 61%), mp 206–207◦C after recrystallization from hexane.
(Found: [M + H]+ 605.3750. C39H54ClO3 requires [M+] 605.3761).
δH 1.16 (s, 3H), 1.40 (s, 36H), 2.69 (d, J 13.2, 2H), 3.44 (d, J 13.2, 2H),
5.12 (s, 2H), 6.37 (d, J 8.7, 2H), 6.94 (s, 4H), 7.06 (d, J 8.7, 2H). δC
22.2, 30.2, 34.2, 47.8, 54.8, 127.2, 127.4, 127.5, 128.0, 135.5, 135.6,
139.8, 152.5, 211.0. νmax(KBr)/cm−1 3637, 3020, 2957, 2925, 2875,
1698, 1590, 1435, 1363, 1237, 1156, 1121, 968, 938, 895, 828, 772.
A mixture of 19 (120 mg, 0.1985 mmol) and sodium borohydride
(0.045 g) in ethanol (6 mL) in THF (2 mL) was reacted as above to yield
20 as a white solid (100 mg, 83%), mp 110–112◦C. (Found: [M − OH]+
589.3800. C39H54ClO2 requires [M+] 589.3812). δH 0.77 (s, 3H), 1.47
(s, 18H), 1.48 (s, 18H), 1.99 (br s, 1H), 2.37 (d, J 13.2, 2H), 2.98 (d, J
13.2, 2H), 4.46 (s, 1H), 5.13 (br s, 2H), 6.96 (s, 2H), 7.07 (s, 2H), 7.29
(d, J 8.1, 2H), 7.33 (d, J 8.7, 2H). δC 21.0, 25.6, 30.4, 30.4, 34.2, 40.6,
42.2, 42.5, 67.9, 127.3, 127.5, 127.7, 128.6, 128.9, 129.6, 132.9, 135.2,
135.3, 140.5, 152.1, 152.1. νmax(KBr)/cm−1 3643, 3434, 3020, 2960,
2924, 2873, 1596, 1486, 1435, 1391, 1362, 1234, 1213, 1159, 1121,
1092, 1037, 1014, 884, 800, 770.
2,2-Bis[{3,5-bis(1,1-dimethylethyl)-
4-hydroxy}phenylmethyl]indan-1-ol 16
2,2-Bis[{3,5-bis(1,1-dimethylethyl)-
4-hydroxy}phenylmethyl]indan-1-one 15
1-Indanone (0.53 g, 4 mmol) was added to a mixture of 7 (2 g,
8 mmol) and potassium hydroxide (0.08 g) in methanol (8 mL) at 60◦C
as above. The product was subjected to flash silica gel column chro-
matography using hexane/dichloromethane (1/1) as eluent to give 15
as yellow crystals (1 g, 71%), mp 170–172◦C. (Found: [M + H]+
569.3974. C39H53O3 requires [M+] 569.3995). δH 1.36 (s, 36H), 2.81
(d, J 13.4, 2H), 3.05 (s, 2H), 3.25 (d, J 13.4, 2H), 4.98 (s, 2H), 6.9 (s,
2H), 7.13 (t, J 7.5, 2H), 7.32 (d, J 7.5, 1H), 7.57 (d, J 7.5, 1H). δC 30.2,
34.1, 35.2, 44.1, 55.8, 123.0, 125.7, 126.5, 126.6, 127.9, 134.0, 135.2,
137.8, 152.1, 153.6, 211.4. νmax(KBr)/cm−1 3625, 3575, 2957, 2912,
1702, 1610, 1588, 1466, 1436, 1390, 1361, 1308, 1237, 1213, 1116,
1025, 946, 889, 771, 742.
A mixture of 15 (240 mg) and sodium borohydride (100 mg) in dry
ethanol (6 mL) and THF (2 mL) was reacted as above to give 16 as
colourless crystals (200 mg, 83%), mp 101–103◦C. (Found: [M − OH]+
553.4030. C39H53O2 requires [M+] 553.4046). δH 1.45 (s, 18H), 1.46
(s, 18H), 2.54–2.82 (m, 5H), 2.97 (d, J 13.8, 1H), 5.09 (br s, 2H), 5.13 (s,
1H), 6.8 (s, 2H), 7.03 (s, 2H), 7.1 (d, J 7.5, 1H), 7.18 (t, J 7.5, 2H), 7.32
(d, J 7.5, 1H). δC 30.4, 34.2, 37.4, 37.9, 41.5, 53.8, 123.5, 124.5, 126.4,
127.1, 127.3, 129.2, 129.3, 135.2, 135.7, 140.6, 144.5. νmax(KBr)/cm−1
3642, 3448, 3020, 2958, 2922, 2876, 1435, 1391, 1317, 1234, 1156,
1121, 886, 758.
Acknowledgments
J.K. is grateful for support from Urmia and Flinders
Universities for study leave; N.M.P. is grateful to Austaid
for a postgraduate scholarship.
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