Synthesis of oxetane/azetidine containing spirocycles

Article abstract of DOI:10.1016/j.tetlet.2019.03.042

Oxetane-benzopyran spirocycles were synthesised via a palladium catalysed cyclisation-cross coupling cascade reaction whilst oxetane/azetidine-pyrrolidino isoindolone spirocycles were synthesised via a silver catalysed 1,3-dipolar cycloaddition reaction f

Full text of DOI:10.1016/j.tetlet.2019.03.042

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Synthesis of oxetane/azetidine containing spirocycles
Rosalie Hamill, Benjamin Jones, Christopher M. Pask, Visuvanathar Sridharan
PII:
S0040-4039(19)30258-8
https://doi.org/10.1016/j.tetlet.2019.03.042
TETL 50683
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Reference:
Tetrahedron Letters
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12 March 2019
15 March 2019
Please cite this article as: Hamill, R., Jones, B., Pask, C.M., Sridharan, V., Synthesis of oxetane/azetidine containing
spirocycles, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.03.042
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Synthesis of oxetane/azetidine containing spirocycles
Rosalie Hamill, Benjamin Jones, Christopher M. Pask and Visuvanathar Sridharan*

1
Tetrahedron Letters
Synthesis of oxetane/azetidine containing spirocycles
Rosalie Hamill, Benjamin Jones, Christopher M. Pask, and Visuvanathar Sridharan*
School of Chemistry, University of Leeds, LS2 9JT, UK.
*Corresponding author: v.sridharan@leeds.ac.uk; Tel: +44 1133436520
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Oxetane-benzopyran spirocycles were synthesised via a palladium catalysed cyclisation-cross
coupling cascade reaction whilst oxetane/azetidine-pyrrolidino isoindolone spirocycles were
synthesised via a silver catalysed 1,3-dipolar cycloaddition reaction followed by a palladium
catalysed carbonylation-amination process.
Available online
2018 Elsevier Ltd. All rights reserved.
Keywords:
Oxetane
Spirocycle
Cycloaddition
Carbonylation
Introduction
Oxetane rings in drug molecules have been determined to
have an influence on a multitude of different properties,
including lipophilicity, aqueous solubility, metabolic stability,
and conformational preference; they also greatly improve key
pharmacokinetic properties when grafted onto molecular
scaffolds.1 Oxetanes also demonstrate diverse potential as
bioisosteres for less desirable functional groups in drug design,
such as gem-dimethyl and carbonyl groups. The potential for
oxetanes to be used as gem-dimethyl bioisosteres was introduced
by Carreira and co-workers;2 it is common practice in drug
discovery to introduce gem-dimethyl groups into metabolically
labile methylene units. However, this also adds to the molecules
lipophilicity, and can adversely affect its pharmacokinetic
properties. Use of an oxetane instead of a gem-dimethyl group,
bridging the two methyl groups with an electronegative oxygen,
has been shown to add the desired bulk without altering the
overall lipophilicity.2 Furthermore, the Van der Waals volume of
an oxetane is almost identical to that of the gem-dimethyl group,
and their partial molar volumes in water are essentially identical.3
Benzopyran derivatives have been shown to have notable
Figure 1. Representative examples of drug molecules containing the
benzopyran motif and oxetane/pyrrolidine spirocycles.
In this communication we report (i) a palladium catalysed
cyclisation-cross coupling cascade reaction for the synthesis of
oxetane-benzopyran spirocycles (Scheme 1a) and (ii) a silver
catalysed 1,3-dipolar cycloaddition reaction followed by a
palladium catalysed carbonylation amination process to afford
oxetane/azetidine-pyrolidino isoindolone containing spirocycles
(Scheme 1b, c).
bioactivities,
including
anti-inflammatory
and
anti-
hypertensiveproperties.4 Benzopyrans can be found in
a
multitude of divergent areas within chemistry; such as the
metabolite eriodictyol, which has anti-inflammatory and
antioxidant properties,5 and the phytoalexin xanthyletin, which is
found in citrus plants6 (Fig. 1). Oxetane/pyrrolidine containing
spirocycles are important structural motifs, possessing a wide
range of medicinal properties including anti-viral7 and anti-
bacterial8 (Fig. 1).
Palladium catalysed cyclisation-cross coupling cascade
reactions were used to synthesise benzopyran spirocycles with a
tethered oxetane moiety.9 Initially we explored the palladium
catalysed cyclisation-cross coupling process using 1 (1 mmol),
phenyl boronic acid (2 mmol), Pd(OAc)2 (10 mol%), dppf (10
mol%) and Cs2CO3 (2 mmol) in dioxane/water (15:1, 3 mL)

2
Tetrahedron
stirred at 90 °C for 16 h, which gave the cyclisation-cross
coupling product 3a together with the direct capture product 3b
in 85% combined yield (Table 1, entry 1) favouring the
cyclisation-cross coupling product 3a. Cyclisation-cross coupling
reactions using 1 and p-methoxyphenyl boronic acid gave the
cyclisation-cross coupling product 3c together with the direct
capture product 3d in 50% combined yield (Table 1, entry 2)
whilst m-trifluoromethylphenylboronic acid gave the cyclisation-
cross coupling product 3e and the direct capture product 3f in
24% combined yield (Table 1, entry 3). The lower yields of
products 3c and 3d may be partly due to the boronic acid
containing an electron withdrawing group and therefore
undergoing protodeborylation at a faster rate.
2
50
1a
3
24
1a
However, when a Boc-protected azetidine was tethered to
alkene 2 only the direct capture products 3g and 3h were
observed (Table 1, entries 4, 5) in moderate yield suggesting that
the transmetallation step occurs faster than the carbopalladation
step (Scheme 1a). This is proposed to be due to the difference in
puckering angle between the azetidine (≈33o) and oxetane (11o)
rings.10
4
55c
1b
30c
5
1b
aReagents and conditions: 1 (1 mmol), boronic acid (2 mmol),
Pd(OAc)2 (10 mol%), dppf (10 mol%), Cs2CO3 (2 mmol),
dioxane/water (15:1, 3 mL), 90 °C, 16 h; bIsolated yield. cThe use of
Pd(PPh3)4 (10 mol%) also gave the direct capture product.
Next, we explored a silver catalysed 1,3-dipolar cycloaddition
reaction followed by a palladium catalysed carbonylation
amination process to afford oxetane/azetidine-pyrolidino
isoindolone spirocycles (Scheme 1b). Initially we carried out the
silver catalysed 1,3-dipolar cycloaddition reaction using methyl-
(E)-N-[(2-iodophenyl)methylene]glycinate (0.5 mmol), methyl 2-
(oxetan-3-ylidene)acetate (0.5 mmol), Ag2O (10 mol%) and DBU
(0.5 mmol) in toluene (10 mL) at room temperature for 16 h,
which gave the cycloadduct 4a in 71% yield (Table 2, entry 1).
Scheme 1. Palladium and silver catalysed cascade reactions.
Table 1. Palladium catalysed cyclisation-cross coupling cascade.a
Product
Yield
(%)b
Entr
y
Zipp
er
Boronic acid
The reaction is stereospecific and regiospecific, affording a
single isolated product.11 One regioisomer is preferentially
formed because of the favourable HOMO-LUMO overlap
between the dipole and dipolarophile in the endo-transition state
of the syn-dipole (Scheme 2).12 A single diastereomer was also
1
85
1a
observed
using
tert-butyl-3-(2-methoxy-2-
oxoethylidene)azetidine-1-carboxylate 4c as
a dipolarophile
(Table 2, entry 3).

3
6
31
7
46
Scheme 2. Formation of the metallodipole.
aReagents and conditions: imine (0.5 mmol), dipolarophile (0.5
mmol), DBU (0.5 mmol), Ag2O (10 mol%), toluene (15 mL), room
temperature 16-20 h. bIsolated yield.
Imines derived from alanine methyl ester/leucine methyl ester
also underwent the cycloaddition reaction with oxetane/azetidine
dipolarophiles to give cycloadducts 5d and 5e in moderate yields
(Table 2, entries 4-5). We also varied the activating group in the
imine. Thus, the 2-pyridyl activating group resulted in the
formation of cycloadducts 5f and 5g in moderate yields (Table 2,
entries 6-7).
Finally we explored the palladium catalysed carbonylation-
amination reaction (Scheme 1c).13 Thus, 5f (1 mmol), Cs2CO3 (2
mmol), Pd(OAc)2 (10 mol%) and tris 2-furyl phosphine (20
mol%) under a carbon monoxide balloon (1 atm.) in toluene at
100 °C for 24 h, afforded the expected carbonylated product 6a
and the epimerised carbonylated product 6b in a 1:1 ratio and
31% combined yield (Scheme 3). The structure of 6b was
confirmed by single crystal X-ray diffraction (Fig. 3).14
Table 2. Silver catalysed 1, 3-dipolar cycloaddition reaction.a
Entr
y
Imine
Cycloadduct
Yield
(%)b
1
71
2
53
Scheme 3. Palladium catalysed carbonylation/amination reaction.
3
4
46
52
Figure 2. Single X-ray crystal structure of compound 6b.
Epimerisation could occur before or after the carbonylation
process. The reaction of cycloadduct 5g and carbon monoxide (1
atm.) also afforded the expected carbonylated product 6c and the
epimerised carbonylated product 6d in a 1:1 ratio and 48%
combined yield. However, cycloadducts 5a-e failed to give
carbonylated products under the same conditions, possibly due to
a sluggish oxidative addition process.
5
25

4
Tetrahedron
8.
Mohamed T., Hosahalli S., Panigrahi S.K., PCT Int.Appl.
WO/2013/148537A1; Chem. Abstr. 2013
In summary, we report the application of a palladium
catalysed cyclisation-cross coupling cascade to synthesise
benzopyran/oxetane spirocycles together with biaryl
containing oxetane/azetidines in moderate to good yields.
Oxetane/azetidine-pyrrolidino isoindolone spirocycles were
9.
Grigg R, Sridharan V. Pure Appl. Chem. 1998; 70: 1047; Grigg R,
Sridharan V. J. Organomet. Chem. 1999; 576: 65; Li Z, Hu C,
Guo J, Li J, Cui Y, Jia Y. Org. Lett. 2010; 12: 480-483; Petrone
DA, Malik HA, Clemenceau A, Lautens M. Org. Lett. 2012;
14:4806-4809
also synthesised via
a
silver-catalysed 1,3-dipolar
cycloaddition reaction followed by a palladium catalysed
carbonylation-amination process in good yields.
10. Smith SA, Hand KE, Love ML, Hill G, Magers DH. J. Comput.
Chem. 2013; 34: 558; Dorofeeva OV, Mastryukov VS, Vilkov
LV, Hargittai I. J. Chem. Soc. Chem. Commun. 1973; 20: 772.
11. Stereochemistry confirmed by NOE studies performed by Jones et
al. on analogous cycloadducts. Results are shown in the ESI.
12. Grigg R, Sridharan V. Adv. in Cycloaddition 1993; 3: 161;
Coldham I, Hufton R. Chem. Rev. 2005; 105: 2765; Najera C,
Sansano JM. J. Angew. Chem. Int. Ed. 2005; 44: 6272; Pandey G,
Banerjee P, Gadre SR. Chem. Rev. 2006; 106: 4484; Aldrio J,
Carretero JC. Chem. Comm. 2014; 50: 12434-12436; Jones B,
Proud M, Sridharan V. Tetrahedron Lett. 2016; 57: 2811; Grigg
R, Sridharan V, Selvaratnam S, Bridge AW. Tetrahedron 1995;
51: 295-306.
Notes and References
1.
2.
Burkhard JA, Wuitschik G, Rogers-Evans M, Muller K, Carreira
EM. Angew. Chem. Int. Ed. 2010; 49: 9052.
Wuitschik G, Rogers-Evans M, Muller K, Fischer H, Wagner B,
Schuler F, Polonchuk L, Carreira EM. Angew. Chem. Int. Ed.
2006; 45: 7736; Wuitschik G, Carreria EM, Wagner B, Fisher H,
Parrilla I, Schuler F, Rogers-Evans M, Muller K. J. Med. Chem.
2010; 53: 3227.
13. Wu, XF Neumann H, Beller M. Chem. Rev. 2013; 113: 1-35
14. Deposition number for compound 20a CCDC 1849751 contains
the supplementary crystallographic data for this structure. This
data can be obtained free of charge from the Cambridge
3.
4.
5.
Edward JT, Farrell PG, Shahidi P. J. Chem. Soc. Farady. Trans.
1977; 73: 705.
Crystallographic
Data
Centre
via
You ZY, Wang YH, Zhang ZG, Xu MJ, Xe SJ, Han TS, Feng L,
Li XG, Xu J. Marine Drugs 2013; 11: 4035.
Rossato MF, Trevisan G, Walker CIB, Klafke JZ, de Oliveria AP,
Villarinho JG, Zanon RB, Royes LFF, Athayde ML, Gomez MV,
Ferrerira J. Biochem. Pharmacol. 2011; 81: 544.
www.ccdc.cam.ac.uk/data_request/cif.
6.
7.
Magiatis P, Melliou E, Skaltsounis AL, Mitaku S, Leonce S,
Renard P, Pierre A, Atassi G. J. Nat. Prod. 1998; 61: 982.
Chen, L., Feng, L., Feng, S., Gao, L., Guo, T., Huang, M., Liu, C.,
Liu, Y., Wang, L., Wong, J., J. C. PCT Int. Appl.
WO/2013/020993; Chem. Abstr. 2013
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5
Highlights
Oxetane/azetidine containing spirocycles are
gaining interest in medicinal chemistry
Stereo/regio-selective
synthesis
of
oxetane/azetidine containing pyrolidines
Creating molecular complexity using simple
starting material