Synthesis of diversely functionalised 2,2-disubstituted oxetanes: Fragment motifs in new chemical space

Article abstract of DOI:10.1039/c5cc05740j

Di-, tri- and tetra-substituted oxetane derivatives with combinations of ester, amide, nitrile, aryl, sulfone and phosphonate substituents are prepared as fragments or building blocks for drug discovery. The synthesis of these novel oxetane functional groups, in new chemical space, is achieved via rhodium-catalysed O-H insertion and C-C bond forming cyclisation.

Full text of DOI:10.1039/c5cc05740j

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DOI: 10.1039/C5CC05740J
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COMMUNICATION
Synthesis of Diversely Functionalised 2,2-Disubstituted Oxetanes:
Fragment Motifs in New Chemical Space
Owen A. Davis, Rosemary A. Croft and James A. Bull*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Di-, tri- and tetra-substituted oxetane derivatives with oxetanes bearing functional groups on the ring are unexplored,
combinations of ester, amide, nitrile, aryl, sulfone and and could provide fascinating new structural units for use by
phosphonate substituents are prepared as fragments or building medicinal chemists. The synthesis of functionalised oxetanes
blocks for drug discovery. The synthesis of these novel oxetane continues to be a challenge. Cyclisation by intramolecular
functional groups, in new chemical space, is achieved via rhodium- Williamson etherification is most common,3 but 2-functionality
catalysed O–H insertion and C–C bond forming cyclisation.
is often precluded due to unstable oxyanionic intermediates.
Also, epoxide-opening and ring-closure methods using
sulfoxonium ylides are not tolerant of sensitive electrophilic
functionality.11 On the other hand, the photochemical
Paterno–Büchi reaction can introduce functionality from an
alkene component, but is often restricted to very highly
substituted oxetanes, with undesirable properties for
medicinal chemistry.12,13,14
We have targeted new oxetane derivatives due their small,
polar nature and well-defined 3-D shape.15 We recently
reported the preparation of 2-sulfonyl oxetanes, formed
through a novel anionic C–C bond forming cyclisation (Scheme
1A).16 These fragments displayed good pH stability, and
stability to liver microsomes.16b We have also established an
efficient synthesis of oxetane 2,2-dicarboxylates involving O–H
insertion using diazomalonates, and C–C bond forming
cyclisation (Scheme 1B).17
Recent years has seen considerable enthusiasm for exploring
new chemical motifs in medicinal chemistry that enter
unexplored chemical and intellectual property (IP) space.1,2
Oxetanes motifs have gained significant traction as desirable
modules for drug discovery.3 Carreira, Rogers-Evans, Müller
and co-workers demonstrated that 3,3-disubstituted oxetanes
constitute polar replacements for gem-dimethyl groups, and
often afford improved solubility and physicochemical
properties.4 Subsequently, oxetane motifs have been adopted
widely in medicinal chemistry programs.5,6 3-Substituted
oxetane motifs have been examined in particular, exploiting
oxetan-3-one3,4 and 3-iodooxetane7 as building blocks. New
spirocycles,8 peptidomimetics9 and other oxetane analogues of
important compounds have been prepared (e.g. Fig 1).10,6
NH2
Cl
O
O
N
Previous work
O
O
S
N
A) 2-(Arylsulfonyl) oxetane fragements (ref 15)
O
LiHMDS
N
O
HO
P
O
N
O
CF3
O O
O
NH
O
3
OH
O
S
O
H
O
Ar
OTs
S
O
O
O
NH2
O
F
Ar
B) Oxetane 2,2-dicarboxylates (ref 16)
EtO2C
oxetano-thalidomide
improved human blood
plasma stability vs thalidomide
3',4'-oxetane nucleoside
inhibitor of Hepatitis C virus
(HCV NS5B; IC50 = 31 mM)
γ-secretase inhibitor
Pfizer
Stepan et al.
R
1) Rh2(OAc)4
(0.5 mol%)
O
HO
X
N2
EtO2C
EtO2C
EtO2C
Fig 1. Biologically active oxetane-containing compounds.
R
2) NaH
C) This work: diversely substituted oxetane motifs
E1
=
E2
CO2R
CONR2
CN
=
Examples of 2-substituted oxetanes remain less studied;
Pfizer reported a class of 2-oxetanyl containing γ-secretase
inhibitors that possessed improved properties relative to
tetrahydrofuran and carbocyclic derivatives.6 However,
1) O–H insertion
R
CONR2
PO(OEt)2
SO2Ph
CN
X
E2
O
HO
R
E1
PO(OEt)2
2) C–C bond forming
cyclisation
E1
N2
(Het)Aryl
E2
Scheme 1. Synthesis of oxetanes through anionic C–C bond forming cyclisation
Here we report the synthesis of unusual oxetane motifs
bearing medicinally relevant functional groups directly on the
ring (Scheme 1C). Diversely functionalised oxetanes in new
chemical space are prepared in a facile manner from
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functionalised diazo compounds by O–H insertion and C–C similarly, to yield the first example of
a 2-oxetanyl
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bond forming cyclisation. These simple but highly phosphonate, 3d.22 Interestingly, the use of nitrile-ester diazo
DOI: 10.1039/C5CC05740J
functionalised motifs provide interesting shape and 1e led to side reactions under the conditions for O–H insertion,
physicochemical properties for fragments or building blocks with the carbenoid undergoing competitive insertion into the
for drug discovery that cannot be prepared by other methods.
benzene solvent (1.2:1–2.4:1 O–H insertion:π-insertion). To
Targeting 2,2-difunctionalised oxetanes, our investigations prevent this unwanted side product, the reaction was
initially focused on a range of unsymmetrical acceptor– performed in CH2Cl2 (25 °C, 17 h), and bromide 2e was isolated
acceptor diazo compounds, with which to examine O–H in 85% yield (entry 5). Cyclisation at 0 °C afforded nitrile
insertion with 2-bromoethanol (Scheme 1C and Table 1).18,19
A
oxetane 3e after 1 h. The sequence was also successful on a
series of diazo compounds 1a-g bearing amide, sulfone, larger scale affording >1.5 g of oxetane 3e in excellent yield
phosphonate, and nitrile groups were prepared from the (entry 6). Mixed nitrile-amide and phosphonate-amide diazo
methylene precursors using TsN3 or TfN3.18,20,21 We first compounds were also successful under the same conditions,
examined amide-ester diazo 1a (entry 1). Pleasingly, using providing oxetanes 3f and 3g respectively (entries 7 and 8).
catalytic Rh2(OAc)4 (0.5 mol%) in benzene at 80 °C successfully The wide variety of substituted oxetanes that can be readily
mediated O–H insertion of the carbene derived from diazo 1a accessed demonstrates the versatility of this approach.
into 2-bromoethanol in 75% yield.
Substituted bromohydrins were then investigated to form
tri- and tetrasubstituted oxetane derivatives (Table 2). The
reaction sequence successfully formed oxetanes with 4-alkyl
(5a) and 4-aryl substituents (5b-e) in good yields using similar
reaction conditions. The additional substituent had little
influence on the O–H insertion step. However, elevated
temperature and increased reaction times were required for
cyclisation of all substituted examples, requiring 16 h at 25 °C
for complete conversion.
Table 1. Scope of 2,2-disubstituted oxetanes varying diazo 1a–g
Rh2(OAc)4
(0.5 mol%)
E2
N2
HO
E2
O
O
NaH
DMF
E2
E1
1a-g
E1
2a-g
PhH. 80 °C
or CH2Cl2, rt
E1
Br
Br
O–H insertion
Cyclisation
3a-g
entry
E1
E2
yield 2
yield 3
oxetane 3
(%)a
(%)b
O
Table 2. Preparation of 2,2,4-, 2,2,3- tri- and 2,2,4,4-tetrasubstituted oxetanes.
EtO2
C
1
2
N
CO2Et
CO2Et
a
b
75
51
93c
O
O
N
R
Rh2(OAc)4
(0.5 mol%)
E2
N2 HO
R
E2
O
R
O
NaH
DMF
O
E2
R
R
E1
E1
4a-h
PhH. 80 °C
or CH2Cl2, rt
E1
5a-h
EtO2C
Br
Br
96c
O
Me
ii)a
N
O
1c–e,h,i
i)
Me
N
MeO
Cl
MeO
O
3
4
SO2Ph
CO2Et
CO2Et
CO2Bn
c
92
87d
70d
EtO2
PhO2
C
OTBS
S
O
O
O
O
F
O
77e
EtO2
(EtO)2OP
C
EtO2C
EtO2C
(EtO)2OP
BnO2C
NC
Et2NOC
PO(OEt)2
CN
d
e
PhO2S
NC
O
85f
88d
i)b 4a 66%
i)d 4b 64%
ii) 5b 71% (dr 54:46)g
i)e 4c 81%
ii) 5c 80% (dr 70:30)g
i)f 4d 63%
ii) 5d 86% (dr 74:26)c,g
5
6
BnO2
C
NC
ii) 5a 92% (dr 55:45)c,g
93f,g
93d,h
O
H
OMe
NC
O
N
7
8
CN
f
67i
84
87d
72d
O
O
O
O
O
N
NBoc
NBoc
PhO2S
BnO2C
NC
i)e 4f 77%
ii) 5f 75% (dr 56:44)c,g
BnO2C
NC
NBoc
Ph
NC
NC
BnO2C
H
O
i)e 4e 80%
ii) 5e 43% (dr 70:30)g
i)b,e 4g 40%
ii) 5g 54%
i)e 4h 65%
ii) 5h 95% (dr 83:17)c,g
(EtO)2OP
O
O
N
PO(OEt)2
g
N
Conditions: i) O–H insertion: 1 (1.1 equiv), β-bromohydrin (0.5–1.3 mmol),
Rh2(OAc)4 (0.5 mol%), PhH, 0.1 M, 80 °C. ii) Cyclisation: 4 (0.3–0.5 mmol), NaH
(1.2 equiv), DMF, 0.025 M, 25 °C, 16 h. adr determined by 1H NMR of crude
reaction mixture. bβ-Chlorohydrin used. cOxetane isomers separated by silica
chromatography. d1.5 equiv diazo. eRun in CH2Cl2, 0.1 M at 25 °C for 17 h. f1.2
equiv diazo. g Major diastereoisomer indicated (see ref 23).
aO–H insertion: 1 (1.1 equiv), 2-bromoethanol (1.0–2.0 mmol), Rh2(OAc)4 (0.5
mol%), PhH, 0.1 M, 80 °C. bCyclisation: 2 (0.3–0.6 mmol), NaH (1.2 equiv), DMF,
0.025 M. c0 °C for 1 h; then 25 °C for 1 h. d0 °C for 1 h. e1.5 equiv diazo 1d. fRun in
CH2Cl2, 0.1 M at 25 °C for 17 h. g10 mmol scale. h8 mmol scale. i1.2 equiv diazo 1f.
Cyclisation was then effected by treatment of 2a with NaH
(1.2 equiv, 0 °C, 1 h, then 25 °C, 1 h) to afford 2-amido-2-ester-
oxetane 3a in excellent yield forming the C(2)–C(3) bond. Using
Weinreb amide 1b (entry 2), a slightly reduced yield was
obtained for the O–H insertion (51%), but an excellent yield
was obtained on cyclisation of 2b to oxetane 3b. Sulfone-ester
diazo 1c smoothly underwent O–H insertion, followed by
cyclisation in just 1 h at 0 °C to provide a new type of sulfonyl
oxetane (entry 3).16 Phosphonate-ester diazo 1d proceeded
For oxetanes 5a and 5b, a ~1:1 mixture of diastereoisomers
was obtained due to the sterically similar ester-sulfone or
ester-phosphonate groups.23 Diazo compounds with a less
sterically demanding nitrile group (1e, 1h, 1i) gave increased
diastereoselectivity (up to 3:1 dr). The incorporation of a 3-Ph
group gave the 2,2,3-substituted derivative 5f (dr = 56:44).
2,2,4,4-Tetrasubstituted oxetane 5g was prepared from the
commercially available chlorohydrin (1-chloro-2-methyl-2-
propanol) in moderate yields. The synthesis of novel fused
2 | J. Name., 2012, 00, 1-3
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bicyclic oxetane scaffold 5h started by treating N-Boc-3- derivatives will be reported in due course. We gratefully
View Article Online
DOI: 10.1039/C5CC05740J
pyrroline with NBS and H2O to provide 3-bromo-4-hydroxy- acknowledge EPSRC (CAF, EP/J001538/1; Impact Acceleration
pyrrolidine, which gave ether 4h on O–H insertion. Cyclisation Account, EP/K503733/1), and Imperial College London. We
then afforded the bicyclic oxetane 5h as a 83:17 mixture of thank EPSRC National Mass Spectrometry Facility, Swansea.
separable diastereoisomers in 95% combined yield.21,23
Table 3. Scope of 2-aryl-oxetane 2-carboxylates
Next we examined aryl-ester (donor–acceptor) diazo
compounds,24 to generate 2-aryl-oxetane-2-carboxylates
(Table 3). Such aryl-substituted heterocycles offer attractive
features for fragment screening and are little studied in
medicinal chemistry.25 To our delight, the O–H insertion
conditions were effective for the phenyl-ester diazo 6a with an
excellent 86% yield using reduced Rh2(OAc)4 loading (0.25
mol%, entry 1). The O–H insertion was successful across varied
aryl groups (entries 3-8), including the chloropyridyl diazo 6f.
However, using the NaH in DMF conditions for cyclisation gave
variable yields and oxetane 8a and bromide 7a proved
inseparable. Alternative bases and conditions were
examined,21 and the use of LiHMDS (1.4 equiv) in THF was
found to give quantitative conversion to oxetane 8a with a
93% isolated yield (entry 1). This reaction sequence was
similarly successful on a larger scale (entry 2). The modified
cyclisation conditions worked well for substituted aryl
derivatives including halogenated (entries 4–5), and pyridyl
derivatives (entry 8). However, the electron rich p-methoxy
phenyl substrate (entry 6) led to low conversion and isolated
yield. Using a larger excess of LiHMDS (2 equiv) gave an
improved yield of 41% (entry 7). The cyclisation conditions
were also effective for aryl-amide ether 7g (entry 9). This
approach provided direct access to compounds that conform
well to fragment guidelines for fragment screening.21
Rh2(OAc)4
(0.25 mol%)
LiHMDS
(1.4 equiv)
E
N2 HO
E
O
O
E
THF
PhH. 80 °C
Ar
Ar
7a-g
Ar
8a-g
Br
Br
6a-g
entry
Ar
Ph
Ph
E
yield 7
yield 8
oxetane 8
(%)a
(%)b
O
EtO2
C
1
2
86
93
CO2Et
a
b
80c
76d
O
iPrO2
C
3
4
CO2iPr
87e
69
72
97
O
EtO2
C
3-ClPh
CO2Et
c
Cl
O
EtO2
C
5
4-CF3Ph
CO2Et
CO2Et
CO2Et
d
64
86
54
77
F3
C
O
EtO2
C
6
7
22
4-MeOPh
e
f
41f
MeO
O
EtO2
C
As a more divergent approach to similar compounds,
hydrolysis of ester oxetane 8a was examined (Scheme 2a).
Using NaOH afforded sodium salt 9 as an attractive oxetane
containing building block. Amide coupling with morpholine,
directly from the salt,26 gave amide 10 in a good yield over two
steps. Finally, we prepared additional 2-nitrile oxetane
8
9
76
90
N
N
Cl
Cl
O
O
N
O
O
N
3-ClPh
g
73
O
derivatives.
The nitrile group is receiving considerable
Cl
attention in drug discovery,27,28 being metabolically robust and
a strong hydrogen bond acceptor. Therefore, we considered
that the combination with an oxetane motif could present a
fascinating structure for medicinal chemistry.13,29 From nitrile-
oxetane benzyl ester 3e, ester hydrolysis was best achieved
using LiOH to afford lithium salt 11 (Scheme 2b). Amide bond
formation gave nitrile amide oxetanes 12 and 13 in 30-35%
yields over 2 steps. Importantly, treatment of oxetane 3f with
TFA promoted Boc deprotection, 14, without other
degradation, providing encouraging preliminary information
on acid stability (Scheme 2c; 10 equiv TFA, 22 h).
In summary, we have developed a versatile strategy to
prepare diversely functionalised oxetane derivatives, involving
O–H insertion and C–C bond forming cyclisation. A wide variety
of functional groups have been introduced on the oxetane
ring, accessing new chemical space. We believe these oxetane
motifs will provide interesting new structural elements for
medicinal chemistry programs as well as synthesis. Efforts
towards enantioselective synthesis and studies on the stability
and medicinal chemistry properties of the new oxetane
aO–H insertion: 6 (1.1–1.5 equiv), 2-bromoethanol (0.4–2.0 mmol), Rh2(OAc)4
(0.25 mol %), PhH, 0.1 M, 80 °C. bCyclisation: 7 (0.3–0.5 mmol), LiHMDS (1.4
equiv), THF, 0.025 M, 0 °C, 1 h. cReaction on 7.5 mmol scale. dReaction on 5.0
mmol scale. e0.5 mol % Rh2(OAc)4. f2.0 equiv LiHMDS.
a)
O
O
O
O
morpholine, HATU
DIPEA, DMF, 25 °C
78% (2 steps)
NaOH
N
EtOH, 30 °C
EtO2C
NaO2C
Ph
Ph
Ph
O
9
10
8a
O
b)
H
N
cyclobutyl amine
30% (2 steps)
O
O
CN
LiOH•H2O
O
O
HATU, DIPEA
DMF, 25 °C
12
BnO2C
LiO2C
THF, H2O
25 °C
O
p-anisidine
H
N
CN
CN
PMP
35% (2 steps)
3e
11
CN
13
c)
O
TFA
O
NC
O
NC
O
CH2Cl2, 25 °C
79%
N
N
3f
14
NBoc
NH
Scheme 2. Divergent synthesis of oxetane derivatives
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