Strain-Release-Driven Homologation of Boronic Esters: Application to the Modular Synthesis of Azetidines

Article abstract of DOI:10.1021/jacs.9b01513

Azetidines are important motifs in medicinal chemistry, but there are a limited number of methods for their synthesis. Herein, we present a new method for their modular construction by exploiting the high ring strain associated with azabicyclo[1.1.0]butane. Generation of azabicyclo[1.1.0]butyl lithium followed by its trapping with a boronic ester gives an intermediate boronate complex which, upon N-protonation with acetic acid, undergoes 1,2-migration with cleavage of the central C-N bond to relieve ring strain. The methodology is applicable to primary, secondary, tertiary, aryl, and alkenyl boronic esters and occurs with complete stereospecificity. The homologated azetidinyl boronic esters can be further functionalized through reaction of the N-H azetidine, and through transformation of the boronic ester. The methodology was applied to a short, stereoselective synthesis of the azetidine-containing pharmaceutical, cobimetinib.

Full text of DOI:10.1021/jacs.9b01513

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Strain-Release-Driven Homologation of Boronic Esters:
Application to the Modular Synthesis of Azetidines
Alexander Fawcett, Amna Murtaza, Charlotte H. U. Gregson, and Varinder K. Aggarwal
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b01513 • Publication Date (Web): 05 Mar 2019
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Strain-Release-Driven Homologation of Boronic Esters: Application
to the Modular Synthesis of Azetidines
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Alexander Fawcett, Amna Murtaza, Charlotte H. U. Gregson, and Varinder K. Aggarwal*
School of Chemistry, University of Bristol, Cantock’s Close, Bristol BS8 1TS, United Kingdom
Supporting Information Placeholder
ABSTRACT: Azetidines are important motifs in medicinal chem-
istry, but there are a limited number of methods for their synthesis.
Herein, we present a new method for their modular construction by
exploiting the high ring strain associated with azabicyclo[1.1.0]bu-
tane. Generation of azabicyclo[1.1.0]butyl lithium followed by its
trapping with a boronic ester gives an intermediate boronate com-
plex which, upon N-protonation with acetic acid, undergoes 1,2-mi-
gration with cleavage of the central C–N bond to relieve ring strain.
The methodology is applicable to primary, secondary, tertiary, aryl
and alkenyl boronic esters, and occurs with complete stereospeci-
ficity. The homologated azetidinyl boronic esters can be further
functionalized through reaction of the N−H azetidine, and through
transformation of the boronic ester. The methodology was applied
to a short, stereoselective synthesis of the azetidine-containing
pharmaceutical, cobimetinib.
Nitrogen-containing heterocycles are the most prevalent and im-
portant heterocycles in medicinal chemistry, as evidenced by their
presence in approximately 60% of U.S. FDA approved small-mol-
ecule drugs. Among this class of compounds, the saturated heter-
Figure 1. (A) Selected azetidine-containing pharmaceuticals.
1
(
B) Strain-release 1,2-metalate rearrangement of bicyclo[1.1.0]bu-
ocycles piperidine and pyrrolidine are some of the most commonly
encountered. However, their four-membered ring analogue, azet-
tyl boronate complexes. (C) This work: strain-release 1,2-metalate
rearrangement of azabicyclo[1.1.0]butyl boronate complexes.
2
idine, is much less prevalent, despite possessing a range of desira-
ble characteristics; its small, strained ring structure confers struc-
tural rigidity and fewer rotatable bonds, which has been shown to
correlate with increased bioavailability, and they have been
We recently reported the homologation of boronic esters by a cy-
clobutane unit by using bicyclo[1.1.0]butyl lithium (Figure 1B).
1
3
3
It was shown that bicyclo[1.1.0]butyl lithium could react with bo-
ronic esters to form highly strained bicyclo[1.1.0]butyl boronate
complexes, which then underwent 1,2-metalate rearrangement
upon treatment with electrophilic palladium(II)-aryl complexes to
ultimately form a range of diastereomerically pure borylated cyclo-
butanes. The 1,2-metalate rearrangement is driven by relief of the
high ring strain of the bi-cycle. We reasoned that the power inher-
ent in the relief of ring strain could be harnessed to drive 1,2-met-
demonstrated to exhibit greater metabolic stability and improved
4
physicochemical properties relative to their larger ring analogues.
Indeed, the azetidine moiety is featured in several pharmaceuticals,
5
6
7
including cobimetinib (1), azelnipidine (2) and baricitinib (3)
Figure 1A), as well as in biologically-active natural products.8
However, despite these attractive features, there is a dearth of meth-
(
2
,9
ods available to prepare azetidines. Some current methods in-
clude inter- and intramolecular alkylation of amine nucleophiles,
reduction of -lactams, and the aza Paternò-Büchi reaction.
14
alate rearrangements in other related ring systems. In particular,
2
10
we were interested in the use of nitrogen-containing analogues of
bicyclo[1.1.0]butyl lithium, such as azabicyclo[1.1.0]butyl lithium
(4), since this would potentially enable the homologation of bo-
ronic esters to give synthetically- and pharmaceutically-important
azetidines bearing a versatile boronic ester moiety (Figure 1C).
However, such a nucleophilic species (azabicyclo[1.1.0]butyl lith-
ium, 4) has not been previously reported. Reactions involving the
parent azabicyclo[1.1.0]butane (5) are dominated by nucleophilic
Therefore, the development of new methodologies that facilitate
the modular synthesis of azetidines from common building blocks
would be highly attractive, particularly in advancing medicinal
1
1
chemistry programs. Herein, we describe a method to homologate
readily available boronic esters with azabicyclo[1.1.0]butyl lithium
(
a novel species) to form versatile borylated azetidines, which can
then be diversified through transformation of the amine and boronic
1
2
15
ester functional groups.
ring opening, which break the strained central C−N bond.
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ca. 6 ppm in the 11B NMR spectrum of the reaction mixture. Sur-
prisingly, the boronate complex 10 did not undergo spontaneous
,2-metalate rearrangement, despite the high strain energy that
would be released upon ring opening. We therefore needed to make
the amine into a better leaving group and so explored different
activating reagents. Addition of benzyl chloroformate at low tem-
perature followed by warming did result in complete conversion of
the boronate complex but gave an inseparable mixture of boronic
and borinic esters 11 and 12, resulting from C-and O-migration re-
spectively, in a 1.5:1.0 ratio and a combined 92% NMR yield
Scheme 1. (A) Lithiation of azabicyclo[1.1.0]butane and its
trapping to form a sulfoxide. (B) Reaction optimization.
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(Scheme 1B, entry 1). Benzoyl chloride behaved similarly (entry
2
). By contrast, we were pleased to find that simple protonation of
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the boronate complex with acetic acid resulted in exclusive C-mi-
gration and, following protection with a Boc group, azetidine 11
was obtained in 78% NMR yield (Scheme 1B, entry 3). The added
benefit of this approach is that it generates an unprotected N−H
azetidine intermediate, which can then be reacted in any desired
manner. Further improvements were achieved by switching the sol-
vent to THF and modifying the stoichiometry of the reagents
(
1.2 equivalents of 8 and tert-butyl lithium). The N−H azetidine
products were easily separated from the sulfoxide by-product by
filtering through a plug of silica gel: the azetidine acetic acid salt
was retained on the silica and all other compounds eluted (‘silica
catch’ method). The top layer of the silica gel plug was then col-
lected and subjected to Boc protection, giving pure 11 in 80% iso-
lated yield (1.39 g, 3.81 mmol, Scheme 1B, entry 4). It was also
discovered that the reaction could be triggered using TsOH which
enabled purification of the azetidine by precipitation of the tosylate
salt without using the ‘silica catch’ purification (entry 5, see Sup-
porting Information for details).
The robustness of these optimized conditions is illustrated by the
preparation of over 25 unique azetidines (Scheme 2B). The scope
of the boronic ester component was first explored and was found to
encompass a broad range of primary, secondary and tertiary bo-
ronic esters. The range of primary boronic esters included n-alkyl
a
NMR yield. b Followed by Boc protection. c Isolated yield.
Gram-scale (4.76 mmol).
d
(
13), allylic (14), benzylic (15) and methyl (16), the latter being an
1
9
In order to form azabicyclo[1.1.0]butyl lithium, we reasoned that
the C−H bond at the bridgehead of 5 would be the most acidic, since
it has the greatest s-character, and so could be selectively lithi-
important substituent in medicinal chemistry. The methyl group
2
0
is normally a poor migrating group and so we were concerned that
competing O-migration might occur, as had been observed when
using benzyl chloroformate as an activating reagent. However, ex-
clusive C-migration was observed when using acetic acid as the ac-
tivator with this challenging substrate to give 16 in modest yield.
Notable secondary boronic esters included an -amino boronic es-
ter, giving azetidine 23 featuring a piperidine substituent in 54%
yield, and -alkoxy boronic ester, giving 3-oxypropylamine 24 in
59% yield, both of which are motifs present in previously reported
16
ated. However, this route raised significant concerns since the
strongly nucleophilic species, azabicyclo[1.1.0]butyl lithium,
could potentially react with 5 to trigger a polymerization reac-
1
5a,n
tion.
To this end, it was discovered that azabicylo[1.1.0]butane,
2
1
generated in situ from ammonium salt 6 by treatment with phenyl
1
5l
lithium at −78 °C,
ium/TMEDA at −78 °C to form azabicyclo[1.1.0]butyl lithium
4). We elected to trap 4 as a sulfoxide, since this would potentially
offer a stable, solid reagent from which 4 could be conveniently
could be lithiated using s-butyl lith-
1
7
5,22
(
azetidine-containing pharmaceuticals.
The tertiary boronic es-
ters included tert-butyl (27), adamantyl (28), substituted cyclobutyl
1
3
13
23
regenerated. Therefore, 4 was trapped with methyl 4-methylben-
zenesulfinate (7) to give azabicyclo[1.1.0]butyl sulfoxide 8 in 62%
yield (Scheme 1A). Sulfoxide 8 was formed as a single regioiso-
mer, showing that selective deprotonation had indeed occurred, and
problems relating to polymerization did not materialize, presuma-
bly due to a fast, low temperature lithiation step. The reaction was
scalable and, as anticipated, 8 was a stable, easy-to-handle crystal-
line compound.
(29), bicyclo[2.2.2]octyl (30), dimethyl phenyl silyl (31), and a
2
4
doubly benzylic (32) boronic ester, giving the azetidine products
in good to excellent yields. It was also possible to regioselectively
2
5
homologate the primary boronic ester of a 1,2-bis(boronic ester),
giving 1,3-bis(boronic ester) 33, and perform a mono-homologa-
26
tion of a 1,1-bis(boronic ester), giving 1,2-bis(boronic ester) 34,
27
in moderate yields. The enantiospecificity (e.s.) of the transfor-
mation was demonstrated using two enantioenriched boronic es-
ters, which gave products 18 and 32 with complete retention of ste-
reochemistry (100% e.s.). Furthermore, four diastereomerically
pure boronic esters were homologated to give the corresponding
azetidine products, 20, 25, 26 and 29, with complete diastereospec-
With the azabicyclo[1.1.0]butyl sulfoxide 8 in hand, its conversion
to azabicyclo[1.1.0]butyl lithium and subsequent reaction with cy-
clohexyl pinacol boronic ester 9 was investigated. Treatment of a
mixture of 9 and 1.3 equivalents of 8 in 2-methyl tetrahydrofuran
28
ificity (100% d.s.) Aryl and vinyl boronic esters could also be
1
3
at −78 °C with 1.3 equivalents of tert-butyl lithium and then al-
lowing the reaction mixture to stir for two hours resulted in com-
plete boronate complex formation, as evidenced by a single peak at
29
employed, giving the desired azetidines 35−38 in good yields.
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Scheme 2. Substrate scope of the azetidine homologation of boronic esters. (A) Optimized reaction conditions. (B) Boronic
ester substrate scope. (C) Reaction performed without use of sulfoxide.
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All reactions were performed using 0.24 mmol of the boronic ester and all yields refer to isolated material. a NMR yield. PMP = para-
methoxyphenyl. e.s. (enantiospecificity) = [e.e. of product/e.e. of starting material] × 100%. d.s. (diastereospecificity) = [d.e. of product/d.e.
of starting material] × 100%.
3
3
Finally, we explored whether the reaction could be achieved di-
rectly from the ammonium salt 6, thereby by-passing the sulfoxide
intermediate 8, which could be more convenient when a single azet-
idine product is required. Thus, treatment of the ammonium salt 6
with phenyl lithium, followed by sec-butyl lithium/TMEDA, cy-
clohexyl pinacol boronic ester, acetic acid and finally Boc protec-
tion, gave the homologated azetidine boronic ester product 11 in
incorporate a pyridine (50) and formation of trifluoroborate salt
24
51 (Figure 2B). In all cases, good to excellent yields of the func-
tionalized azetidines were achieved. Finally, a deboronative fluor-
ination was performed, yielding fluorinated azetidine 52 in mod-
erate yield. Fluorinated amines are important motifs since the fluo-
rine atom can lead to beneficial modulation of the molecules’ phys-
3
4
3
5
a
ical and chemical properties, including the pK of the amine.
6
8% yield (Scheme 2C).
Finally, to showcase the application of this new method we targeted
We next demonstrated that a range of different transformations of
the preparation of cobimetinib (1), an MEK inhibitor used in the
treatment of melanoma. Starting from ammonium salt 6, azabicy-
clo[1.1.]butyl lithium 4 was prepared by deprotonation (see
Scheme 2C) and reacted with (R)-N-Boc piperidyl 2-pinacol bo-
5
the nitrogen atom of the intermediate N−H azetidine is possible
(Figure 2A). In addition to the Boc protecting group, the nitrogen
atom could also be protected with the tosyl (39) and Cbz (40) pro-
tecting groups in good yields. An amide coupling reaction with
benzoic acid, using HATU as the coupling reagent, gave 41 also in
21,36
ronic ester 53
to give the N−H azetidine intermediate 54. Sub-
5
sequent in situ acylation of 54 with the required acid fluoride de-
livered boronic ester 55 in 62% yield and with complete enanti-
ospecificity. Finally, oxidation with basic peroxide gave alcohol 56
in 89% yield, and subsequent Boc deprotection gave cobimetinib
(Scheme 3). This asymmetric synthesis of cobimetinib is shorter
than previously reported routes, and provides a modularity that
3
0
good yield. A representative Buchwald−Hartwig cross-coupling
using 4-bromobenzonitrile gave aniline 42 in 71% yield. The inter-
mediate could also be engaged in S Ar reactions with a range of
hetero)aryl halides to give 44−49 in good yields. These reaction
classes are among the most commonly used reactions within the
N
5
(
37
31
field of medicinal chemistry.
potentially enables facile preparation of analogues through use of
different boronic esters, acid halides, and/or boronic ester transfor-
mations.
To demonstrate the synthetic utility of the borylated azetidine prod-
ucts, azetidinyl boronic ester 11 was subjected to a range of repre-
sentative boronic ester transformations, including oxidation to the
In conclusion, we have developed a procedure that enables the
modular construction of a diverse family of azetidines by the
3
2
corresponding alcohol (48), vinylation (49),
arylation to
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AUTHOR INFORMATION
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Corresponding Author
v.aggarwal@bristol.ac.uk
*
ORCID
Alexander Fawcett: 0000-0003-1880-3269
Varinder K. Aggarwal: 0000-0003-0344-6430
Present Addresses
†Department of Chemistry, Quaid-i-Azam University, Islamabad-
4
5320, Pakistan.
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Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENTS
We thank EPSRC (EP/I038071/1) and H2020 ERC (670668) for
financial support. A.M thanks the Commonwealth Scholarship
Commission UK for a PhD Split Site Scholarship 2017−2018. We
thank Steven H. Bennett for technical support and Dr A. Noble for
proofreading.
Figure 2. Synthetic transformations of borylated azetidines. (A)
Alternative reactions at nitrogen. See Scheme 1A for conditions to
form the acetic acid ammonium salt intermediate. Abbreviated re-
a
b
action conditions: TsCl, Et
PhCOOH, N,N-diisopropylethylamine, HATU; Tosic acid salt
3
N; benzyl chloroformate, Et
3
N;
c
d
e
used, Pd
X = F or Cl), Et
the substrate. Abbreviated reaction conditions: H
2
(dba)
3
, Xantphos, 4-bromobenzonitrile, NaOtBu; Ar-X
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(
3
N. (B) Boronic ester transformations using 11 as
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g
2
O
2
/NaOH; vi-
h
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= para-toluenesulfonyl.
2
, then NaOMe; ArLi, then 2,2,2-trichloroethyl
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Supporting Information
The Supporting Information is available free of charge on the ACS
Publications website.
Detailed experimental procedures, and characterization data for
new compounds (PDF).
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