Expanding the medicinal chemistry toolbox: stereospecific generation of methyl group-containing propylene linkers

Article abstract of DOI:10.1016/j.tetlet.2006.08.020

Use of alkyl substituted propylene linkers as a strategy for fine-tuning the biological activity of medicinal agents requires ready access to these substrates. Herein, a general strategy is described for stereospecifically generating 18 chiral mono- and d

Full text of DOI:10.1016/j.tetlet.2006.08.020

Tetrahedron Letters 47 (2006) 7285–7287
Expanding the medicinal chemistry toolbox: stereospecific
generation of methyl group-containing propylene linkers
Kristopher Bosse, Jason Marineau, Deane M. Nason, Anton J. Fliri, Barb E. Segelstein,
Kishor Desai and Robert A. Volkmann*
Pfizer Global Research and Development, Groton Laboratories, Pfizer Inc, Groton, CT 06340, United States
Received 11 February 2006; revised 9 August 2006; accepted 9 August 2006
Available online 30 August 2006
Abstract—Use of alkyl substituted propylene linkers as a strategy for fine-tuning the biological activity of medicinal agents requires
ready access to these substrates. Herein, a general strategy is described for stereospecifically generating 18 chiral mono- and di-meth-
ylpropylene linkers. All twelve vicinal 1,2-propylene targets were generated from methyl-3-hydroxybutanoate and all 1,3-disubsti-
tuted targets from pentane-2,4-diol.
Ó 2006 Elsevier Ltd. All rights reserved.
A number of strategies exist in medicinal chemistry for
optimizing a molecule’s biological profile. Rigid struc-
tural templates can favor the binding of ligands to pro-
teins by ensuring the precise spatial orientation of
important functional groups (pharmacophores). Flexi-
ble templates, however, also have an important role in
disease intervention and rely on specific ligand confor-
mations to achieve the same goal. In fact, many natural
products and existing and potential drugs fall into this
category. Favoring specific low-energy conformations
of non-rigid molecules, however, is particularly chal-
lenging especially if key functional groups are separated
by alkyl bridges bearing a number of rotating bonds. Be-
cause of the conformational flexibility of non-rigid
molecules, strategies attempting to exploit specific
ligand conformations are primarily guided by in silico
predictors since closely related templates required to sys-
tematically investigate structure–function relationships
are not available.
aryloxy moieties in a number of SSRI (selective seroto-
nin reuptake inhibitors) antidepressants such as fluoxe-
tine and S-duloxetine (Fig. 1). In addition, they have
also been employed to couple basic groups such as pip-
erazines and piperidines with aromatic moieties in a
number of antipsychotic drugs (i.e., fluphenazine and
domperidone, Fig. 1). Inserting methyl substituents on
propylene linkers provides an attractive option for
influencing the spatial orientation between groups at
either end of the alkyl chain without dramatically affect-
ing molecule size or lipophilicity.
Cl
OH
N
NH
N
N
O
O
N
N
HN
N
S
Herein, we provide a synthetic strategy for generating
intermediates which provide an avenue for investigating
the influence of acyclic conformational control on bio-
logical activity. The methodology provides propylene
linkers containing methyl groups in all three positions
of the chain. Substituted three carbon atom bridges were
chosen for this investigation since they link amino and
Fluphenazine
Domperidone
O
O
CF3
S
S-Duloxetine
HN
HN
Fluoxetine
*
Corresponding author. Tel.: +1 860 441 4662; e-mail: robert.a.
volkmann@pfizer.com
Figure 1. Medicines containing alkyl linkers.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.08.020

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K. Bosse et al. / Tetrahedron Letters 47 (2006) 7285–7287
In total, 18 chiral aryloxyalkylamines (all the possible
chiral propylene linkers containing one or two methyl
groups) have been prepared. Having a general method
for accessing the entire set of mono and 1,2- and 1,3-di-
methyl propylene spacers within a series with docu-
mented biological activity (SRI) not only provides an
opportunity for assessing the viability of the acyclic ste-
reocontrol approach for fine-tuning biological activity in
a series, but also provides valuable synthetic intermedi-
ates for accessing chiral 3-aminopropanols, 1,3-propane-
diols, and 1,3-propanediamines.
ether formation to generate 5 and a subsequent dimeth-
ylamine-mediated bromine displacement. Interestingly,
switching the sequence of the Mitsunobu and amination
steps resulted in erosion of the optical purity of the
product, implicating the intermediacy of the achiral
1,1,3-trimethylazetidinium intermediate A.4 Accord-
ingly, Mitsunobu condensation of (S)- and (R)-3-(di-
methylamino)-2-methylpropan-1-ol with 3,4-dichloro-
phenol provided product ee’s of 65–67%. The remaining
monomethyl substituted aryloxyalkyldimethylamine 9
was prepared by selective monotosylation5 of (S)-bu-
tane-1,3-diol 7 followed by a Mitsunobu-enabled sec-
ondary ether formation to provide tosylate 8.
Dimethylamine-mediated tosylate displacement cleanly
provided 9.
To ensure that the chemistry selected to access substi-
tuted propylene linkers would not only service our needs
but would be broadly applicable to other related ap-
proaches, practical routes involving a minimal number
of chiral starting materials were targeted. In the case
of dimethyl substituted linkers, the intent was to exploit
the reactivity difference between primary and secondary
alcohols to control the regiospecificity of the reaction
and obviate the need for protecting groups. Stereospe-
cific Mitsunobu1 and tosylate/mesylate displacements
were chosen to incorporate phenoxy and amine substit-
uents at secondary carbon atoms to ensure stereochem-
ical integrity (inversion) at these centers.
Propylene linkers containing vicinal dimethyl groups
were accessed from readily available (S)-methyl-3-
hydroxybutanoate 10.6 Alkylation of the dianion of 10
with methyl iodide using conditions described by Frater
provided 11.7 Ester reduction with lithium aluminum
hydride followed by selective alcohol tosylation
(1.05 equiv tosyl chloride, À15 °C) afforded tosylate
12.5,8 Alcohol differentiation via selective tosylation
allows for incorporation of amine and aryloxy substitu-
ents at either end of the propyl chain. Tosylate dis-
placement by substituted phenoxides followed by
tosylation of the secondary alcohol and amination with
dimethylamine yielded 13. Treatment of 12, on the other
hand, with phenols under Mitsunobu conditions to
generate the corresponding aryl ether followed by
tosylate displacement by dimethylamine afforded 14
(Scheme 2).
Stereospecific incorporation of a single methyl substitu-
ent in the propyl chain was easily achieved from com-
mercially available starting materials (Scheme 1).
Conversion of butanoic acid 12 to alcohol 2 proceeded
smoothly via sodium borohydride reduction of the
mixed anhydride generated from 1. Reduction of 2 with
lithium aluminum hydride followed by Mitsunobu con-
densation of the primary alcohol with substituted phe-
nols provided dimethylamine 3.3 Preparation of
isomeric dimethylamine 6 was achieved in two steps
from (R)-3-bromo-2-methylpropan-1-ol 4 following aryl
Inversion of the secondary alcohol center in 11 provides
an opportunity to generate the remaining set of diaste-
reomeric aryloxypropylamines. Treatment of (2S,3S)-
methyl-3-hydroxy-2-methylbutanoate 11 with 3,5-dini-
trobenzoic acid using standard Mitsunobu conditions9
yielded 3,5-dinitrobenzoate 1510 (Scheme 3). Identical
conditions utilized for the preparation of monotosylate
12 from 11 were utilized for converting 15 to 16. In addi-
tion, conditions used for the syntheses of 13 and 14 were
also utilized for the preparation of 17 and 18.
O
Cl
O
N
1)
O
O
BOCN
OH
DME -15 oC
1
2) NaBH4 / 93%
Me2N
Br
OAr
BOCN
Br
OH1) LiAlH4 / Et2O
2
3
1) LiAlH4/Et2O
2) TEA/DMAP/TsCl
CH2Cl2 / 60%
2)ArOH/DEAD/
PPh3 /THF/ 37%
2 LDA/MeI/DMPU
THF/-78 oC/78%
OH
O
OH
O
OAr
ArOH/DEAD
OH
OMe
OMe
11
PPh3 /THF/ 80%
5
4
10
1) ArOH/Cs2CO3/TBAI
acetone/65 oC/75%
2) TEA/TsCl/DMAP
3) NHMe2/ iPrOH
83 oC/29%
(CH3)2NH/iPrOH
H2O/83 oC/80%
NMe2
13
Me2N
OAr
6
N
+
A
OAr
OH
OH
1) TsCl/TEA/DMAP/CH2Cl2/77%
2) ArOH/DEAD/PPh3/THF/63%
OTs
HO
12
OAr
7
1) ArOH/DEAD
Ph3P/ CH2Cl2/70%
2) NHMe2/ iPrOH
83 oC/ 47%
OAr
OAr
(CH3)2NH/H2O
83 oC/ 73%
NMe2
14
Me2N
TsO
9
8
Ar = 2-Me-4-F-Ph
Ar = 2-Me-4-F-Ph
Scheme 1. Preparation of aryloxyalkylamines 3, 6, and 9.
Scheme 2. Preparation of aryloxyalkylamines 13 and 14.

K. Bosse et al. / Tetrahedron Letters 47 (2006) 7285–7287
7287
Acknowledgements
O
O2N
DNBA/Ph3P
O
O
1) LiAlH4/ Et2O
2) TEA/DMAP
We are grateful to Jotham W. Coe and Professor Steven
V. Ley for stimulating discussions.
OMe
11
TsCl/CH2Cl2/59%
DEAD/THF/28%
15
NO2
Supplementary data
NMe2
1) ArOH/Cs2CO3
TBAI/ acetone
2) TEA/TsCl/DMAP
3) NHMe2/ iPrOH
34%
OAr
Synthetic procedures for the preparation of all interme-
diates and products. Supplementary data associated
with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2006.08.020.
17
OH
OTs
1) ArOH/DEAD
Ph3P/CH2Cl2/70%
OAr
16
NMe2
2) NHMe2/ iPrOH
83 oC/40%
18
References and notes
Ar = 3,4-Cl2-Ph
1. For examples of Mitsunobu reactions involving secondary
centers, see: (a) Falkiewicz, B.; Kolodziejczyk, A. S.;
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Liebigs Annalen/Recueil 1997, 7, 1371–1379.
Scheme 3. Preparation of aryloxypropylamines 17 and 18.
OH OAr
20
OH OH
ArOH/DEAD/PPh3
THF/51%
19
Me2N
OAr
1.) MesOH/DEAD/PPh3/THF/85%
2.) NHMe2/iPrOH/83 oC/70%
3. Ibuki, T.; Sugihara, T.; Kawakubo, H.; Sone, T. U.S.
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4. Both enantiomers of 3 were generated and ratios were
determined by chiral HPLC.
21
1.) TsCl/TEA/DMAP/CH2Cl2/76%
2.) NHMe2/iPrOH/83 oC/43%
Me2N
OAr
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22
Ar = 2-Me-4-F-Ph
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Scheme 4. Preparation of 1,3-dimethylsubstituted 21 and 22.
The final targets bearing methyl substituents at both
ends of the propylene chain were generated from
(2S,4S)-pentane-2,4-diol 19. Mitsunobu condensations
with substituted phenols provided (2S,4R)-4-phenoxy-
pentan-2-ol 20.11 Having set the stereochemistry for
the aryloxy substituent allows the preparation of both
diastereomeric amines 21 and 22 from 20. Treatment
of 20 with methanesulfonic acid under Mitsunobu con-
ditions12 yielded intermediate mesylate (via inversion)
which upon dimethylamine treatment provided 21. Stan-
dard tosylation conditions (TsCl, TEA, DMAP, CH2Cl2)
followed by dimethylamine treatment generated 22
(Scheme 4).
9. (a) Mitsunobu, O. Synthesis 1981, 1, 1–28; (b) Mori, K.;
Watanabe, H. Tetrahedron 1985, 41, 3423–3428.
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8, 821–826.
In summary, an efficient strategy has been developed for
the synthesis of structurally related aryloxyalkylamines
containing 18 chiral propylene linkers. While syntheses
of the 2-methyl-4-fluoro- and 3,4-dichlorophenyl ana-
logs are reported herein, the methodology has been em-
ployed to access other amine and phenyl analogs. In
addition, intermediates described herein provide ready
access to chiral 3-aminopropanols, 1,3-propanediols,
and 1,3-propanediamines.
12. Davis, A. P.; Dresen, S.; Lawless, L. J. Tetrahedron Lett.
1997, 38, 4305–4308.