Strain-Release Driven Spirocyclization of Azabicyclo[1.1.0]butyl Ketones

Article abstract of DOI:10.1002/anie.202102754

Due to their intrinsic rigidity, three-dimensionality and structural novelty, spirocyclic molecules have become increasingly sought-after moieties in drug discovery. Herein, we report a strain-release driven synthesis of azetidine-containing spirocycles by harnessing the inherent ring strain of the azabicyclo[1.1.0]butane (ABB) fragment. Novel ABB-ketone precursors bearing silyl-protected alcohols were synthesized in a single step and shown to engage in electrophile-induced spirocyclization-desilylation reactions. Primary, secondary and tertiary silyl ethers were effectively transformed into a library of new spiro-azetidines, with a range of substituents and ring sizes. In addition, the products are generated with synthetically useful ketone and protected-amine functional groups, which provides the potential for further elaboration and for this chemistry to be utilized in the rapid assembly of medicinally relevant compounds.

Full text of DOI:10.1002/anie.202102754

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Communications
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How to cite: Angew. Chem. Int. Ed. 2021, 60, 11824–11829
International Edition:
German Edition:
doi.org/10.1002/anie.202102754
doi.org/10.1002/ange.202102754
Spiro Compounds
Strain-Release Driven Spirocyclization of Azabicyclo[1.1.0]butyl
Ketones
Jasper L. Tyler, Adam Noble, and Varinder K. Aggarwal*
Abstract: Due to their intrinsic rigidity, three-dimensionality
and structural novelty, spirocyclic molecules have become
increasingly sought-after moieties in drug discovery. Herein,
we report a strain-release driven synthesis of azetidine-
containing spirocycles by harnessing the inherent ring strain
of the azabicyclo[1.1.0]butane (ABB) fragment. Novel ABB-
ketone precursors bearing silyl-protected alcohols were syn-
thesized in a single step and shown to engage in electrophile-
induced spirocyclization-desilylation reactions. Primary, sec-
ondary and tertiary silyl ethers were effectively transformed
into a library of new spiro-azetidines, with a range of
substituents and ring sizes. In addition, the products are
generated with synthetically useful ketone and protected-amine
functional groups, which provides the potential for further
elaboration and for this chemistry to be utilized in the rapid
assembly of medicinally relevant compounds.
S
pirocyclic molecules are gaining considerable interest
within medicinal chemistry discovery programs, emanating
from the constant drive to develop new and unusual scaffolds
that populate regions of unexplored chemical space.[1] In
contrast to well-studied aromatic ring-based structures, which
are inherently two-dimensional, the sp3-rich nature of a spiro-
cycle is such that the exit vectors of a single unit can populate
the third dimension; a feature that has been shown to improve
clinical success in drug candidates.[2,3] The rigidity imparted
from the inclusion of four-membered rings, such as an
azetidine, also provides a well-defined spatial disposition of
the substituents for highly predictable vectorization.[4] The
identification of such advantageous properties has fuelled
a surge in reports of biologically active spirocycle-based
molecules, with a number of azetidine-containing spirocyclic
lead compounds entering clinical trials or gaining approval as
pharmaceuticals (Figure 1a).[5]
Figure 1. a) Selected azetidine-containing spirocyclic pharmaceuticals.
b) Previous work: (i) electrophile-induced ring opening of ABB and (ii)
ABB-Li in the synthesis of azetidinyl boronic esters. c) This work:
strain-release driven spirocyclization of azabicyclo[1.1.0]butyl ketones.
LG=leaving group.
typically through alkylation,[7] cycloaddition,[8] metal-cata-
lyzed cyclization onto alkenes or alkynes,[9] or ring-closing
metathesis reactions.[10] Another limitation is the difficulty in
forming highly functionalized spiro-azetidines that would be
amenable to additional structural diversification. Such frag-
ments would represent highly valuable building blocks that
could facilitate the application of spiro-azetidines in medic-
inal chemistry programs.[11]
An emerging strategy for the construction of azetidines is
the use of azabicyclo[1.1.0]butane (ABB).[12,13] Upon electro-
philic activation of the nitrogen of ABB, this “spring-loaded”
fragment shows strong electrophilicity at the bridgehead
carbon, where nucleophilic addition is driven by cleavage of
the highly strained central bond (Figure 1b,i).[14] We recently
reported that lithiation of ABB to give azabicyclobutyl-
lithium (ABB-Li, 1) effectively converts the bridgehead
carbon into a strong nucleophile, thus providing a highly
strained carbenoid species that was applied to the synthesis of
1,3-substituted azetidine boronic esters (Figure 1b,ii).[15]
We were eager to further investigate the carbenoid-like
reactivity of ABB-Li and considered its application in the
Despite these attractive features, there is a limited range
of approaches available for the synthesis of spiro-azetidines.[6]
Current strategies often involve lengthy syntheses of tethered
cyclic molecules before invoking a further ring-closing step,
[*] J. L. Tyler, Dr. A. Noble, Prof. V. K. Aggarwal
School of Chemistry, University of Bristol
Cantock’s Close, Bristol, BS8 1TS (UK)
E-mail: v.aggarwal@bristol.ac.uk
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202102754.
ꢀ 2021 The Authors. Angewandte Chemie International Edition
published by Wiley-VCH GmbH. This is an open access article under
the terms of the Creative Commons Attribution License, which
permits use, distribution and reproduction in any medium, provided
the original work is properly cited.
11824
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expedient and modular construction of azetidine-containing
(Scheme 1). In general, higher yields were obtained when
spirocycles. We postulated that the coupling of ABB-Li to an
electrophile containing a nucleophilic atom would provide an
intermediate predisposed to strain-release driven spirocycli-
zation reactions, thus providing a novel approach to access
spiro-azetidines from two ambiphilic coupling partners.
Herein, we report the addition of ABB-Li to silyl-protected
alcohol-containing carboxylate esters and Weinreb amides to
generate a novel class of stable azabicyclo[1.1.0]butyl ketones
(ABB-ketones). Upon electrophilic activation, these species
engaged in an intramolecular spirocyclization event with
concomitant oxygen desilylation to provide a diverse range of
spiro-azetidine products (Figure 1c).
We began by investigating the synthesis of ABB-ketones 3
by the reaction of carboxylic acid derivatives 2 with ABB-Li
(1), which was formed in situ from commercially available
ammonium salt 5.[15–17] Pleasingly, this allowed the single-step
construction of a wide variety of ABB-ketones bearing a (3a–
c), b (3d–q), g (3r), and d (3s) silyl-protected alcohols
using Weinreb amides (2, LG = N(Me)OMe) as the electro-
phile; however, in the case of a-oxy ketone products 3a–c and
aryl ketone products 3t–v, moderate to good yields could also
be obtained when readily available carboxylate esters (2,
LG = OMe, OEt) were used. The specific choice of silyl group
was principally dictated by its proficiency in the following
spirocyclization step (vide infra), which was found to be
facilitated by the use of the readily cleavable TMS group.
However, in the synthesis of several a- and b-oxy ketones
(3a–f), and aryl ketones 3t–v, TMS ethers were too labile
under the reaction conditions, necessitating the installation of
more robust protecting groups (TES/TBS). Surprisingly,
ABB-ketones 3a–v were found to be stable to chromato-
graphic purification, in contrast to related azabicyclo-
[1.1.0]butyl carbinols.[16]
With a range of silyl ether-containing ABB-ketones in
hand, we subsequently investigated the proposed spirocycli-
zation reaction. ABB-ketone 3a was selected as the model
substrate, as azaspiro[3.3]heptanes are highly sought-after in
drug discovery programs due to their favorable pharmacoki-
netic properties compared to commonly employed hetero-
cyclic isosteres.[18] We also anticipated that spirocyclization to
generate a four-membered ring would be more challenging
than for larger ring analogues and so the solution here would
be more broadly applicable. We hypothesized that, upon
activation of the ABB nitrogen atom, interaction of the
oxygen lone pair of the tethered silyl ether with the strongly
electrophilic bridgehead carbon would facilitate concomitant
desilylation, allowing for a single step spirocyclization proce-
dure from the easily accessible ABB-ketones.
Immediately, it became apparent that careful selection of
the electrophile used for N-activation was required (Table 1.
see Supporting Information for full optimization study). We
found that employing either 2,2,2-trichloroethoxycarbonyl
chloride (TrocCl) or HBr gave exclusively 3-halo-azetidines 6
Table 1: Optimization of the spirocyclization–desilylation reaction.[a]
Entry Electrophile (equiv) Conditions
4: % Yield 6: % Yield
1
2
3
4
5
6
7
TrocCl (1.2)
HBr (1.2)
BF3·OEt2 (1.2)
Tf2O (2.0)
TFAA (2.0)
TFAA (2.0)
TFAA (2.0)
TFAA (2.0)
TFAA (1.5)
TFAA (3.0)
08C, 0.5 h
0
0
87
76[b]
0
53
0
0
0
0
0
rt, 16 h
À788CÀ08C, 2 h 0[c]
À788C, 0.5 h
À788C, 0.5 h
À788C, 3 h
À788C, 24 h
À788C, 3 h
À788C, 3 h
À788C, 3 h
21
36
65 (61)[d]
61
24
43
50
8[e]
9
Scheme 1. Preparation of ABB-ketones from 1. All reactions were
carried out using ammonium salt 5 (1.0 mmol) in THF (3.6 mL),
trimethylsilyl (TMS), triethylsilyl (TES) and tert-butyldimethylsilyl (TBS)
ethers, 2, were added as 1.0 M solutions in THF. Isolated yields given.
[a] From the corresponding ethyl ester. [b] From the corresponding
Weinreb amide. [c] The diastereomeric ratio (dr) was determined by
1H NMR analysis of the crude reaction mixture. The dr of Weinreb
amides was >20:1 [d] From the corresponding methyl ester.
10
0
[a] All reactions were carried out using 3a (0.10 mmol) in CH2Cl2
(1.0 mL). Yields were determined by H NMR analysis using dibromo-
methane as an internal standard. [b] Yield determined after protection of
the azetidine with di-tert-butyl dicarbonate (Boc2O). [c] Only uncharac-
terized oligomers were observed. [d] Isolated yield. [e] With 2,6-lutidine
(2.0 equiv).
1
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(entries 1 and 2).[14] Unfortunately, all attempts to convert 6 to
the desired spirocycle upon silyl deprotection were unsuc-
cessful, therefore, we sought alternative activators in an
attempt to suppress this undesired reactivity. Lewis acids, such
as boron trifluoride, failed to induce spirocyclization, instead
forming uncharacterized oligomeric species (entry 3).[19]
Gratifyingly, treatment of 3a with triflic anhydride (Tf2O)
at À788C provided spirocycle 4 in 21% yield, alongside the
corresponding triflate 6 (entry 4). The yield of 4 was increased
to 36% upon switching to trifluoroacetic anhydride (TFAA),
which also prevented the formation of side-product 6
(entry 5).[20] Further improvements were accomplished by
extending the reaction time, with a maximum yield (65%)
achieved after 3 hours at À788C (entries 6 and 7). Altering
the equivalents of TFAA or the addition of base were both
found to be deleterious to the reaction (entries 8–10). The
discovery that TFAAwas optimum was particularly fortuitous
since the trifluoroacetamide product can be easily depro-
tected to unveil the free azetidine.[21]
alcohols also underwent high yielding spirocyclization to form
disubstituted spirocycle 4c. The reaction was also amenable
to scale-up, with 4a isolated in comparable yield when
prepared on a gram-scale. Extending the carbon chain to
access oxa-azaspiro[3.4]octanes was highly favorable under
the same single-step spirocyclization–desilylation procedure,
highlighting the modularity of the approach. Primary alcohol
substrates bearing methyl (4d), aromatic (4e) and dimethyl
(4 f) substitution patterns all performed well in the reaction
from the corresponding TES ethers. However, secondary
alcohol substrates were more effectively transformed into the
spirocyclic products when employing TMS as the protecting
group (4g–n). A variety of functionalities were tolerated at
the carbonyl b-position including aromatic (4j), heteroaro-
matic (4k), alkenyl (4l) and heteroatom (4m, 4n) substitu-
ents. It should be noted that in the case of 4n, the yield was
diminished by competing cyclization and debenzylation of the
benzyl ether moiety, forming the corresponding oxa-azaspiro-
[3.5]nonane in 15% yield. Tertiary alcohols could also be
employed, providing 4o and dispirocyclic compound 4p in
excellent yields.
Having established optimal conditions, we then inves-
tigated the scope of the reaction (Scheme 2). In addition to
secondary alcohol-derived substrates, which provided methyl
(4a) and benzyl (4b) monosubstituted products, tertiary
One of the key benefits of spirocyclic scaffolds over
aromatic-based molecules in drug discovery is that the sp3-
Scheme 2. Substrate scope for the spirocyclization–desilylation reaction of ABB-ketones. All reactions were carried out using 3 (0.10 mmol) in
CH2Cl2 (1.0 mL). Isolated yields given. [a] From the corresponding TES ether. [b] From the corresponding TMS ether. [c] From the corresponding
TBS ether. [d] Gram-scale reaction was carried out with 3a (4.0 mmol) in CH2Cl2 (20 mL). [e] Also observed 15% NMR yield of oxa-
azaspiro[3.5]nonane. [f] The dr was determined by 1H NMR analysis of the crude reaction mixture. The dr of ABB-ketones was >20:1. [g] With 2,6-
lutidine (2.0 equiv). [h] Trace product was detected by high resolution mass spectrometry. Reaction performed at 0.02 M concentration. [i] Isolated
as the trifluoroacetic acid salt. [j] From the TMS protected ABB-carbinol. The TMS group was cleaved upon work-up.
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Table 2: Investigation of suboptimal substrates and comparison of
protecting groups.
rich nature provides the opportunity to exploit point chir-
ality.[22] We therefore wanted to explore whether the spiro-
cyclization–desilylation process is stereoretentive. We ration-
alized that the stereochemical integrity of both the a- and b-
positions could be simultaneously probed by monitoring the
diastereomeric ratio (dr) of an a,b-disubstituted substrate
throughout the synthesis. To this end, syn-3q and anti-3q were
submitted to the spirocyclization reaction to provide syn-4q
and anti-4q, respectively. Pleasingly, no change in dr was
observed,[23] showing that the stereochemical integrity of the
substrate is fully maintained during the spirocyclization–
desilylation process.
Entry
1
SiR3
4: % Yield[a]
7: % Yield[b]
TMS: 3h
TMS: 3j
TES: 3h’
TES: 3j’
35
44
17
80
44
2
3
4
Ph
Ph
42
5[b]
In addition to the formation of trifluoroacetyl-protected
azetidines, the synthesis of sulfonamide products 4aa, 4bb
and 4cc was achieved by employing triflic anhydride as the
activator, albeit with decreased yields due to competing
nucleophilic substitution at the bridgehead carbon of the
ABB by the triflate anion (see Table 1, entry 4). Despite the
weak nucleophilic character of the triflate anion, addition is
nevertheless observed, presumably due to the increased
electrophilicity of the ABB bridgehead carbon upon activa-
tion with triflic anhydride, resulting in a less selective
reaction.[16] Further extension of the carbon chain gave
access to oxa-azaspiro[3.5]nonane 4r in 90% yield. However,
cyclization to form the corresponding 7-membered ring
product 4s occurred in only trace amounts. Finally, the
scope was broadened to include aryl alcohol-based nucleo-
philes. TBS-protected phenol (4t), 3-pyridinol (4u’) and
naphthol (4v) substrates were all transformed into the
spirocyclic products in good to excellent yields. Notably, in
the case of 4u, the ketone adjacent to the pyridine was prone
to nucleophilic addition and subsequent side reactions (see
Supporting Information for details). However, this decom-
position could be prevented by employing the analogous
TMS-protected ABB-carbinol, which was readily deprotected
upon work-up to give alcohol 4u’.
During our investigations into the substrate scope, we
were intrigued by the significant disparity in yields between
seemingly similar substrates. For example, cyclopropyl prod-
uct 4h was formed in only 35% yield, compared to a 94%
yield for isopropyl product 4i. A comparably low yield of
42% was also obtained for phenyl substituted product 4j.
Further investigation into the diminished yields for the
spirocyclization of both cyclopropyl ABB-ketone 3h and
phenyl ABB-ketone 3j revealed that trifluoroacetates 7h and
7j were the major side products formed in these reactions
(Table 2, entries 1 and 2). Interestingly, repeating these
reactions with a bulkier silyl group (TES) almost entirely
suppressed product formation and further increased the
amount of side product detected (entries 3 and 4). This
drastic effect, and formation of the corresponding side
products, was not observed in other secondary silyl ether
substrates, where the more hindered silyl protecting group
simply resulted in a slight decrease in yield (see Supporting
Information for details).
trace
[a] Isolated yield. [b] Yields were determined by 1H NMR analysis using
dibromomethane as an internal standard.
Scheme 3. Proposed mechanism for the spirocyclization–desilylation
reaction.
ophilic substitution. Intramolecular attack of the silyl ether
then ensues to construct the challenging spirocenter and give
oxonium intermediate II, which is driven by the relief of the
highly strained central bond of the ABB. Alternatively,
intermolecular substitution at the bridgehead carbon by
a trifluoroacetate anion to generate 6 (Pathway a) is also
possible and can be detected for substrates where a tethered
nucleophile is absent. We initially considered the possibility of
6 as an intermediate in the formation of 4, however,
subsequent attempts to promote this pathway by increasing
the relative concentration of the trifluoroacetate anion with
the addition of tetrabutylammonium trifluoroacetate resulted
in the generation of 6 whilst simultaneously inhibiting
formation of 4, therefore suggesting this species is not an
intermediate on the reaction pathway (see Supporting
Information for details). After spirocyclization, cationic
intermediate II can then undergo a trifluoroacetate-promoted
desilylation to access spirocyclic product 4 (Pathway b). This
proposed cation-induced intramolecular cyclization–desilyla-
tion mechanism of silyl ethers has been previously established
for related cyclization reactions.[24]
To rationalize these observations, we propose the follow-
ing mechanism (Scheme 3). Firstly, trifluoroacyl ammonium
intermediate I is formed upon acylation of the ABB nitrogen
of 3, which activates the bridgehead carbon towards nucle-
If a cation-stabilizing substituent, such as phenyl or
cyclopropyl, is present a to the oxonium in II, then competing
C O bond cleavage occurs to form carbocation III,[25] which is
À
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trapped by a trifluoroacetate anion to give 7 (Pathway c). In
Conflict of interest
this case, when the larger TES group is employed, the rate of
desilylation of II is reduced, therefore favoring Pathway c
over the desired Pathway b. Evidence for the undesired
Pathway c was obtained by the identification and isolation of
7j’. Formation of 7j’ also supports the intermediacy of
The authors declare no conflict of interest.
Keywords: Azabicylo[1.1.0]butanes · Azetidines · Heterocycles ·
Spiro compounds · Strained molecules
À
oxonium II, required to facilitate this C O bond cleavage.
Additionally, the retention of the silyl ether moiety demon-
strates that desilylation does not occur prior to cyclisation but
must be induced by coordination to the activated ABB
system.
Finally, we have demonstrated that the trifluoroacetamide
group can be rapidly cleaved from the azetidine under
exceptionally mild conditions (room temperature, K2CO3,
MeOH:H2O).[21] Using three different classes of spirocyclic
compounds, hydrolysis and tert-butyloxycarbonyl (Boc) pro-
tection was achieved in 67–83% yield (Scheme 4).
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In summary, we have developed a protocol for the
modular construction of a diverse family of azetidine-
containing spirocycles. Novel ABB-ketones were synthesized
in a single step from ABB-Li and found to engage directly in
electrophile-induced spirocyclization reactions. Primary, sec-
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transformed into a library of substituted spiro-azetidines that
incorporated 4-, 5- or 6-membered rings, as well as benzo-
fused ring systems. The ability to preserve stereogenic centers
was also demonstrated by the complete retention of relative
stereochemistry throughout the synthesis. The multitude of
possible points for diversification of the ABB-ketone spiro-
cyclization precursors (substitution pattern, stereochemistry,
tether length), as well as the synthetic utility of the ketone and
azetidine nitrogen in the spirocyclic products, provides the
potential for this chemistry to be utilized in the rapid
assembly of medicinally relevant compounds.
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Acknowledgements
J.T. thanks the Bristol Chemical Synthesis Centre for
Doctoral Training and the EPSRC (EP/G036764/1) for
funding. We thank H. A. Sparkes for X-ray analysis.
´
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Manuscript received: February 23, 2021
Accepted manuscript online: March 22, 2021
Version of record online: April 16, 2021
Angew. Chem. Int. Ed. 2021, 60, 11824 –11829 ꢀ 2021 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH www.angewandte.org 11829