Synthesis of bridged bicyclic amino alcohols as compact modules for medicinal chemistry

Article abstract of DOI:10.1080/00397911.2018.1528615

The efficient synthetic routes of three bridged bicyclic amino alcohols were reported. It is conceivable that these compounds could be readily used as compact modules in medicinal chemistry to fine-tune physicochemical and pharmacokinetic properties, in order to eventually improve the overall quality of small molecule drug candidates.

Full text of DOI:10.1080/00397911.2018.1528615

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Synthesis of bridged bicyclic amino alcohols as
compact modules for medicinal chemistry
Guolong Wu, Di Wang, Wei Zhu, Hong Shen, Haixia Liu & Lei Fu
To cite this article: Guolong Wu, Di Wang, Wei Zhu, Hong Shen, Haixia Liu & Lei Fu (2018):
Synthesis of bridged bicyclic amino alcohols as compact modules for medicinal chemistry,
Synthetic Communications, DOI: 10.1080/00397911.2018.1528615
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https://doi.org/10.1080/00397911.2018.1528615
Synthesis of bridged bicyclic amino alcohols as compact
modules for medicinal chemistry
Guolong Wua,b, Di Wanga, Wei Zhub, Hong Shenb, Haixia Liub, and Lei Fua
b
aSchool of Pharmacy, Shanghai Jiao Tong University, Shanghai, P. R. China; Department of Medicinal
Chemistry, Roche Innovation Center Shanghai, Roche Pharmaceutical Research & Early Development,
Pudong, Shanghai, P. R. China
ABSTRACT
ARTICLE HISTORY
Received 23 July 2018
The efficient synthetic routes of three bridged bicyclic amino
alcohols were reported. It is conceivable that these compounds
could be readily used as compact modules in medicinal chemistry
to fine-tune physicochemical and pharmacokinetic properties, in
order to eventually improve the overall quality of small molecule
drug candidates.
KEYWORDS
Amino alcohol; bridged
bicyclic morpholine;
compact module;
medicinal chemistry
GRAPHICAL ABSTRACT
Introduction
The drug-like properties of amino alcohols have drawn increasing awareness of the
medicinal chemistry community since the introduction of Lipinski’s ‘rule of five’.[1]
Many molecular properties such as molecular weight (MW), lipophilicity (as measured
by LogP for example), polar surface area (PSA), rotatable bonds, and hydrogen bond
donor/acceptor are calculated, evaluated[2], and set within a certain range during the
hit-to-lead and lead-to-candidate optimizations in drug discovery. In addition to those
CONTACT Haixia Liu
haixia.liu@roche.com
Department of medicinal chemistry, Roche Innovation Center
Shanghai, Roche Pharmaceutical Research & Early Development, 720 Cailun Road, Building 5, Pudong, Shanghai 201203,
P. R. China.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher’ website.
ß 2018 Taylor & Francis Group, LLC

2
G. WU ET AL.
Figure 1. Representatives of marketed drugs containing pyrrolidine, piperidine or morpholine.
descriptors, molecular complexity, as measured by the fraction of sp3 carbons (Fsp3)
and the presence of chiral centers may impact the transition of small molecule entities
from discovery stage through clinical investigations to marketed drugs.[3] Taking into
account the potential factors that may have an influence on compound quality, medi-
cinal chemists adopt concepts such as ‘escape from flatland’[3] and conformation restric-
tion[4] in the design and synthesis of novel compact modules with targeted
physicochemical properties, favorable conformations, and pre-set exit vectors for deriva-
tization. These modules may be incorporated into small molecular entities to improve
their quality and performance in various aspects.[5] For example, the recent identifica-
tion of spirocyclic and oxetane containing modules[6] opens up new chemical space and
offers multiple options for medicinal chemists to modulate physicochemical and phar-
macokinetic properties, which may eventually improve the quality of small molecule
drug candidates.
The aliphatic nitrogen-containing heterocycles such as piperidine, morpholine, and
pyrrolidine are the most prevalent structural motifs in the marketed drugs (Figure 1)
and clinical candidates.[7] To explore new chemistry space derived from these classic
scaffolds, we designed a series of bridged bicyclic amino alcohol building blocks, which
contain monocyclic nitrogen aliphatic heterocycle with an attached hydroxyl group
(Figure 2, compound 1–3). We envision that these compact modules will find their
applications in the multidimensional optimization of drug discovery projects. First of
all, these modules adopt compact 3D-shaped conformations which may help the host
molecules to ‘escape from flatland’ and increase solubility and permeability. Moreover,
the bridged tether introduces steric hindrance to the metabolically labile spots, poten-
tially enhancing the building block’s metabolic stability. In the meantime, the tether
may further fill the receptor pockets and increase binding affinity to the protein target.

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3
Metabolic hotspot
pKa:
8.78
10.4
10.51
0.245
ALogP:
−0.529
0.701
3
2
1
pKa:
8.18
8.29
6.56
ALogP:
−0.237
−0.693
−0.467
Figure 2. Calculated molecular properties: pKa, LogP and lowest energy conformations.[8]
In addition, according to the calculated perameters,[8] these modules exhibit distinct
physicochemical properties such as basicity and lipophilicity. Medicinal chemists can
select the appropriate building blocks to fine-tune compound properties. To test their
potential use in drug discovery, we successfully obtained several building blocks and
herein we report our synthetic approach to access these modules.
Retrosynthetic analysis
The retro analysis of compound 1–3 is outlined in Scheme 1 : in general the morpho-
line ring of compound 1–3 can be formed through an acid promoted one-pot deprotec-
tion and ring closure. The advanced intermediate A is converted from compound B by
LiAlH4 reduction, which was obtained by C-alkylation of dicarboxylate C with chloro-
methylbenzyl ether in the presence of LDA. The morpholine derivative D is accessible
through ester reduction of compound E with LiAlH4 which is built up from
SnAP chemistry.[9]
Results and discussion
The synthesis of compound ( )-1 (Scheme 2) commenced with dimethyl pyridine-2,6-
dicarboxylate 4. Hydrogenation in the presence of palladium on carbon followed by
Boc-protection gave cis-substituted piperidine derivative ( )-5 in high yield.[10] The sub-
sequent a-alkylation using benzyl chloromethyl ether afforded the desired mono alky-
lated products as a 1:3 mixture of trans/cis isomers ( )-6a/( )-6b[11] together with
minor double alkylated products 6c/6d.

4
G. WU ET AL.
n
(
)
n
n
n
(
)
(
)
(
)
Alkylation
Cyclization
C
A
B
1: n = 1,
2: n = 0,
E
D
Cyclization
3
Scheme 1. Retrosynthetic approach for compound 1-3.
c
a, b
94%
48%
4
( )-5
( )-6a: trans
( )-6b: cis
6c/6d
ratio of 6a/6b = 1/3
d, e
d, e
80%
Pd/C, H2,
then base
9
( )-7
8
Original planned transformation
h
f, g
81%
42%
( )-1
10
6a and 6b
Scheme 2. Preparation of compound 1. Reagents and conditions: (a) Pd/C, H2, MeOH; (b) (Boc)2O,
toluene, 95 ꢀC; (c) LDA, chloromethylbenzyl ether, THF, ꢁ78 ꢀC to RT; (d) BH3, THF, 0 ꢀC to RT; (e)
MsCl, Et3N, DCM, RT; (f) 1N HCl in EtOAc; (g) LiAlH4, THF, 0 ꢀC to RT; (h) CH3SO3H, 140 ꢀC.

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5
( ) 12a: trans
a
67%
b,c
60%
11
( ) 13
( ) 12b: cis
ratio 12a / 12b = 1/4
d
g
e, f
67%
51%
49%
( ) 2
15
14
Scheme 3. Preparation of compound 2. Reagents and conditions: (a) BnNH2, K2CO3, toluene/water,
80 ꢀC; (b) Pd(OH)2/C, H2, MeOH; (c) (Boc)2O, toluene, 95 ꢀC; (d) LDA, chloromethylbenzyl ether, THF,
ꢁ78 ꢀC to RT; (e) 1N HCl in EtOAc; (f) LiAlH4, THF, 0 ꢀC to RT; (g) CH3SO3H, 140 ꢀC.
Next, we planned to construct the second bridged morpholine ring. A selective reduc-
tion of the less hindered methyl ester of compound ( )-6a with borane followed by
mesylation afforded a bicyclic compound ( )-7 instead of the originally desired mesylate
8. The synthetic strategy was then revised. After Boc-deprotection of the mixture of
compound ( )-6a and ( )-6b, both methyl esters were reduced to give diol 10, which
was treated with MeSO3H at elevated temperature to afford the final building block
( )-1 with modest yield.[12]
Building block ( )-2 is a close analog of compound 1 with one methylene group lesser
at the bridged linker region. A similar synthesis strategy was utilized (Scheme 3). In order
to construct dicarboxylated pyrrolidine 12, treatment of cis-diethyl-2,5-dibromohexane-
dioate with benzylamine and K2CO3 in toluene/water afforded the pyrrolidine product as
a 1:4 mixture of trans/cis isomers ( )-12a/( )-12b.[13–15] The N-Bn group of cis isomer
( )-12 b was switched to N-Boc through a two-step deprotection–protection reaction to
facilitate the subsequent alkylation. Following the same synthetic scheme as described for
compound ( )-6a/( )-6b, the final module ( )-2 was achieved with a moderate yield.
Next, we investigated the synthesis of building block ( )-3 (Scheme 4). By utilizing a
literature procedure and SnAP chemistry,[9] we were able to synthesized compound 16.
Reduction of the ethyl ester of 16 with LiAlH4 afforded alcohol 17, which cyclized to
form the second morpholine ring upon heating in methanesulfonic acid. Unfortunately,
the yield of the final product 3,7-dioxa-9-azabicyclo[3.3.1]nonan-5-ylmethanol ( )-3 was
relatively low.

6
G. WU ET AL.
ref. 15
a
b
90%
13%
16
( )-3
17
Scheme 4. Preparation of compound 4. Reagents and conditions: (a) LiAlH4, THF, 0 ꢀC to RT; (b)
CH3SO3H, 140 ꢀC.
Conclusion
In summary, the synthesis of the three novel bridged amino alcohols was achieved. In our
synthetic strategy, by utilizing commercially available starting materials, we constructed a
5- or 6-membered ring with required functional groups first and then formed the second
bridged morpholine ring under strong acidic cyclization condition without protecting and
differentiating the alcohol groups, which greatly simplified the synthesis. The synthetic
methods described herein are very concise and reproducible, paving the way for their
applications in structure-activity relationship (SAR) and structure-property relationship
(SPR) studies in drug discovery projects. These bridged modules contain embedded pyr-
rolidine, piperidine and morpholine structures. Thus they can serve as novel bioisosteres
for those motifs. Considering their unique 3-dimensional conformations and distinct
physicochemical properties in terms of lipophilicity and basicity, these modules may be
incorporated in analogs in order to solve absorption and safety related issues such as off-
targets, cytotoxicity, hERG, and phospholipidosis. Furthermore, these modules might be
also leveraged to introduce intellectual property (IP) relative to simpler scaffolds. The
application of these building blocks is currently ongoing, and their impacts on biological
targets as well as pharmacokinetics properties will be reported in due course.
Experimental
All reactions involving air-sensitive reagents were performed under an argon atmos-
phere. Analytical thin-layer chromatography was performed using glass plates pre-
coated with silica gel impregnated with a fluorescent indicator and visualized by expos-
ure to ultraviolet light (254 nm) and/or stained by submersion in iodine on silica gel or
aqueous ceric ammonium molybdate followed by heating with a heat gun. Analytical
LC/MS spectra were obtained using a Waters UPLC-SQD Mass. Proton and carbon
nuclear magnetic resonance (1H and 13C NMR) spectra were recorded at 400 MHz on
Brucker spectrometers. Reagents were used as received from commercial suppliers with-
out further purification unless otherwise noted.
Typical experimental procedure for the key compounds
[6-(benzyloxymethyl)-6-(hydroxymethyl)-2-piperidyl]methanol 10
Compound 6a/6b (1.00 g, 2.4 mmol) was treated with HCl in EtOAc (1 N, 60 mL) at
room temperature (RT). The mixture was stirred at RT for 18 h. The solvent was removed
and the residue was purified by plash column chromatography eluting with a gradient of
MeOH/DCM (10:100 to 30:100) to afford dimethyl 2-(benzyloxymethyl)piperidine-2,6-

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7
dicarboxylate (0.84 g, 98%) as a white solid. ESI-HRMS: Calculated for C17H23NO5 [(M þ
1
H)þ]: 322.1576. Found: 322.1677. H NMR (400 MHz, CD3OD) d: 7.39–7.24 (m, 5H),
4.53 (d, J = 0.9 Hz, 2H), 3.91–3.84 (m, 1H), 3.75 (s, 3H), 3.72 (s, 3H), 3.59 (d, J = 9.5 Hz,
1H), 3.38 (dd, J = 3.1, 10.9 Hz, 1H), 2.00–1.90 (m, 1H), 1.86–1.77 (m, 1H), 1.77–1.69 (m,
1H), 1.66–1.49 (m, 2H), 1.48–1.35 (m, 1H). To a solution of dimethyl 2-(benzyloxy-
methyl) piperidine-2,6-dicarboxylate (1.00 g, 3.2 mmol) in THF (50 mL) was added
ꢀ
LiAlH4 (2.0 M in THF, 3.25 mL, 6.5 mmol,) at 0 C. The reaction mixture was then
ꢀ
warmed to RT and stirred overnight. The reaction mixture was then cooled to 0 C and
quenched with aq NaOH (2.0 M, 2 mL). The resulting white precipitate was filtered and
washed with THF (50 mL). The filtrate was dried over Na2SO4 and concentrated under
reduced pressure. The residue was purified by flash column chromatography eluting with
a gradient of MeOH:DCM (10:100 to 30:100) to afford compound 10 (0.70 g, 81%) as a
yellow oil. ESI-HRMS: Calculated for C15H23NO3 [(M þ H)þ]: 266.1678. Found:
266.1772. The product was further purified to give samples of trans- and cis- isomers for
NMR analysis: trans-isomer: 1H NMR (400 MHz, CD3OD) d 7.41–7.32 (m, 4H),
7.32–7.26 (m, 1H), 4.56 (s, 2H), 3.82–3.76 (m, 1H), 3.73–3.66 (m, 1H), 3.55 (dd, J = 4.3,
10.8 Hz, 1H), 3.47 (d, J = 8.9 Hz, 1H), 3.43–3.35 (m, 2H), 3.04–2.89 (m, 1H), 1.77–1.54
(m, 4H), 1.43–1.30 (m, 1H), 1.18–1.05 (m, 1H). 13C NMR (100 MHz, CD3OD) d: 138.2,
1
128.0, 127.4, 127.3, 75.1, 73.2, 65.2, 58.7, 56.5, 51.8, 27.3, 26.9, 18.9. cis-isomer: H NMR
(400 MHz, CD3OD) d 7.29–7.20 (m, 5H), 7.20–7.15 (m, 1H), 4.46 (s, 2H), 3.58 (d, J = 9.5
Hz, 1H), 3.46–3.37 (m, 3H), 3.36–3.31 (m, 1H), 3.28 (dd, J = 7.5, 10.9 Hz, 1H), 2.82 (dt, J
= 3.2, 7.6 Hz, 1H), 1.60–1.48 (m, 3H), 1.47–1.34 (m, 1H), 1.31–1.20 (m, 1H), 1.07–0.92
(m, 1H). 13C NMR (100 MHz, CD3OD) d: 138.2, 128.0, 127.5, 127.3, 73.0, 66.7, 66.5, 65.1,
56.7, 52.1, 27.4, 26.7, 19.0.
3 -oxa-9-azabicyclo[3.3.1]nonan-5-ylmethanol ( )-1
Compound 10 (600 mg, 2.26 mmol) was dissolved in methanesulfonic acid (6 mL). The
solution was heated at 140 ꢀC for 18 h under argon. After cooling to RT, the mixture was
poured slowly into a mixture of ice (15 g) and ꢀwater (15 mL). The mixture was then neu-
tralized with 50% NaOH solution (9 mL) at 0 C. To the mixture was added MeOH (150
mL). The white precipitate was filtered, the filtrate was concentrated under reduced pres-
sure. The residue was purified by spherical C18 column filled with 20–45lm spherical
C18 bonded silica with 100 Å pores using a MPLC system (CombiFlash Companion, Isco
Icn.) eluting with a gradient of MeOH: water (0.5% TFA) (5:100 to 95:100) to afford com-
1
pound ( )-1 (150 mg, 42%) as a light brown oil. H NMR (400 MHz, CD3OD) d
4.11–4.03 (m, 1H), 3.99–3.93 (m, 2H), 3.93–3.87 (m, 1H), 3.51–3.42 (m, 3H), 2.60 (tq, J =
6.4, 13.0 Hz, 1H), 2.14–2.03 (m, 2H), 1.99–1.83 (m, 2H), 1.78–1.71 (m, 1H). 13C NMR
(100 MHz, CD3OD) d 70.2, 67.8, 63.5, 55.7, 48.6, 29.1, 26.2, 18.1. ESI-HRMS: Calculated
for C8H15NO2 [(M þ H)þ]: 158.1103. Found: 158.1175.
[6-(benzyloxymethyl)-6-(hydroxymethyl)-2-piperidyl]methanol 15
Compound 14 (1.00 g, 2.4 mmol) was treated with HCl in EtOAc (1 N, 60 mL) at RT.
The solution was stirred at RT for 18 h, then solvent was removed. The residue was

8
G. WU ET AL.
purified by column chromatography eluting with a gradient of MeOH/DCM (10:100 to
30:100) to the intermediate (0.80 g, quant) as a white solid. 1H NMR (400 MHz,
CD3OD) d 7.42–7.19 (m, 5H), 4.63–4.53 (m, 1H), 4.53–4.45 (m, 1H), 4.24–4.12 (m,
4H), 3.98–3.63 (m, 2H), 3.61–3.44 (m, 1H), 2.24–2.03 (m, 2H), 2.01–1.75 (m, 2H),
1.34–1.20 (m, 6H). To a solution of this intermediate (0.80 g, 2.4 mmol) in dry THF (5
ꢀ
mL) was added LiAlH4 solution (2 M in THF, 2.4 ml, 4.8 mmol) at 0 C. The reaction
mixture was warmed to RT and stirred overnight, then quenched aq NaOH (2 M, 2
mL). The resulting white precipitate was filtered and washed with THF (20 mL). The
filtrate was dried over Na2SO4 and concentrated under reduced pressure. The residue
was purified by flash column chromatography eluting with a gradient of MeOH/DCM
1
(10:100 to 30:100) to afford compound 15 (0.40 g, 67%) as a yellow oil. H NMR (400
MHz, CD3OD) d 7.41–7.33 (m, 4H), 7.31–7.25 (m, 1H), 4.61–4.52 (m, 2H), 3.63–3.56
(m, 1H), 3.56–3.48 (m, 4H), 3.48–3.43 (m, 1H), 3.40–3.35 (m, 1H), 1.96–1.86 (m, 1H),
1.85–1.73 (m, 2H), 1.72–1.59 (m, 1H). IR (neat) vmax 1680, 1353, 1203, 1061, 723 cmꢁ1
ESI-HRMS: Calculated for C14H21NO3 [(M þ H)þ]: 252.1521. Found: 252.1611.
.
3 -oxa-8-azabicyclo[3.2.1]octan-5-ylmethanol ( )-2
Compound 15 (400 mg, 1.59 mmol) was dissolved in methanesulfonic acid (8 mL). The
ꢀ
solution was heated at 140 C for 8 h under argon. After cooling to RT, the mixture
was poured slowly into a mixture of ice (20 g) and water (20 mL), and neutralized with
ꢀ
50% sodium hydroxide solution (24 mL) at 0 C. The mixture was then diluted with
MeOH (200 mL). The formed white precipitate was filtered, the filtrate concentrated
under reduced pressure. The residue was purified by spherical C18 column filled with
20–45lm spherical C18 bonded silica with 100 Å pores using a MPLC system
(CombiFlash Companion, Isco Icn.) eluting with a gradient of Methanol:0.5% TFA in
water (5:100 to 95:100) to afford compound ( )-2 (115 mg, 51%) as a light yellow oil.
1H NMR (400 MHz, CD3OD) d 3.95 (d, J = 5.7 Hz, 1H), 3.90–3.83 (m, 2H), 3.82–3.76
(m, 1H), 3.76–3.65 (m, 3H), 2.25–2.12 (m, 3H), 1.98–1.89 (m, 1H). 13C NMR (100
MHz, CD3OD) d 70.9, 68.4, 67.8, 60.4, 56.5, 26.9, 25.2. IR (neat) vmax 1676, 1203, 1136,
723 cmꢁ1
Found: 144.1026.
.
ESI-HRMS: Calculated for C7H13NO2 [(M
þ
H)þ]: 144.0946.
3 ,7-dioxa-9-azabicyclo[3.3.1]nonan-5-ylmethanol ( )-3
To a solution of compound 16 (0.50 g, 1.9 mmol) in dry THF (30 mL) was added
ꢀ
LiAlH4 (2 M in THF, 1.4 mL, 2.8 mmol) at 0 C. The reaction mixture was warmed to
RT and stirred overnight, then quenched with aq. NaOH (2 M, 1.0 mL). The resulting
white precipitate was filtered and washed with THF (50 mL). The filtrate was dried
over Na2SO4 and concentrated under reduced pressure to afford (9,9-dimethyl-4,8,10-
trioxa-1-azaspiro[5.5]undecan-2-yl)methanol (378 mg, 90%) as a light yellow oil which
was directly used. To this intermediate (110 mg, 0.51mmol) was added methanesulfonic
ꢀ
acid (1 mL). The solution was heated at 140 C for 8 h under argon. After cooling to
room temperature, the mixture was poured slowly into a mixture of ice (5 g) and water
ꢀ
(5 mL), and neutralized with 50% sodium hydroxide solution (3 mL) at 0 C. The

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9
mixture was diluted with methanol (50 mL). The formed white precipitate was filtered,
the filtrate concentrated under reduced pressure. The residue was purified by spherical
C18 column filled with 20–45lm spherical C18 bonded silica with 100 Å pores using a
MPLC system (CombiFlash Companion, Isco Icn.) eluting with a gradient of MeOH/
water (0.5% TFA) (5:100 to 95:100) to afford compound ( )-3 (31 mg, 38%) as a light
1
yellow oil. H NMR (400 MHz, DMSO-d6) d 4.64 (t, J = 5.4 Hz, 1H), 3.82–3.72 (m,
4H), 3.63 (dd, J = 2.9, 10.4 Hz, 2H), 3.41 (d, J = 10.3 Hz, 2H), 3.17 (d, J = 5.3 Hz, 1H),
3.01 (d, J = 5.5 Hz, 2H), 2.68–2.62 (m, 1H). 13C NMR (101 MHz, DMSO-d6) d 72.8,
69.9, 65.6, 51.0, 48.2. IR (neat) vmax 1648, 1048, 1025, 1002, 826, 765 cmꢁ1. ESI-HRMS:
Calculated for C7H13NO3 [(M þ H)þ]: 160.0895. Found: 160.0956.
Acknowledgments
The authors gratefully acknowledge the Hoffmann-La Roche AG and Shanghai Jiao Tong
University for analytical support.
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