Synthesis of sp3-rich chemical libraries based upon 1,2-diazetidines

Article abstract of DOI:10.1016/j.tet.2020.131836

A strategy for the creation of sp³-rich, non-planar scaffolds for drug discovery is described. Stereocontrolled ring opening of homochiral 1,2-epoxides by hydrazine monohydrate followed by selective protection of both nitrogen atoms and Mitsuno

Full text of DOI:10.1016/j.tet.2020.131836

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Synthesis of sp -rich Chemical Libraries based upon 1,2-Diazetidines
Conor Dean, Stefan Roesner, Sundaram Rajkumar, Guy J. Clarkson, Matthew Jones,
Michael Shipman
PII:
S0040-4020(20)31084-X
https://doi.org/10.1016/j.tet.2020.131836
TET 131836
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 4 November 2020
Revised Date: 27 November 2020
Accepted Date: 30 November 2020
Please cite this article as: Dean C, Roesner S, Rajkumar S, Clarkson GJ, Jones M, Shipman
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M, Synthesis of sp -rich Chemical Libraries based upon 1,2-Diazetidines, Tetrahedron, https://
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Graphical Abstract:
1

Title:
Synthesis of sp3-rich Chemical Libraries based upon 1,2-Diazetidines
Authors:
Conor Dean,a Stefan Roesner,a Sundaram Rajkumar,a Guy J. Clarkson,a Matthew Jonesb and
Michael Shipmana
Addresses:
a Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry, CV4 7AL, UK
b Eli Lilly & Company Ltd., Erl Wood Manor, Windlesham, Surrey, GU20 6PH, UK
Corresponding author:
E-mail: m.shipman@warwick.ac.uk
Keywords:
sp3-rich scaffold; chemical library; hydrazine; 1,2-diazetidine; epoxide opening
Dedication:
Dedicated to the memory of Jonathan Williams: a wonderful colleague, mentor and friend
Abstract:
A strategy for the creation of sp3-rich, non-planar scaffolds for drug discovery is described.
Stereocontrolled ring opening of homochiral 1,2-epoxides by hydrazine monohydrate
followed by selective protection of both nitrogen atoms and Mitsunobu ring closure gives
differentially protected, enantiomerically pure 1,2-diazetidines (up to 98% ee) bearing a
variety of C-3 substituents. Iterative C–N functionalization at the two nitrogen atoms using a
range of chemistries and coupling partners produces a 1,2-diazetidine based chemical
library. Crystallographic data confirm that these frameworks display significant sp3-
character with the nitrogen substituents adopting an anti-configuration.
1. Introduction
Success in drug development has been shown to correlate with molecular complexity, as
measured by parameters such as the fraction of saturated carbon atoms (Fsp3) and number
of stereogenic centers.1,2 Consequently, chemical libraries of small molecules capable of
exploring new areas of three-dimensional space have much potential in drug discovery.
Contemporary drug-like libraries such as the ChEMBL dataset often display inadequate
shape diversity and three-dimensionality,2 and hence there is a need to create new
stereochemically-rich compound libraries for application in drug-discovery programs.3
Recently, we introduced a simple way to create chemical libraries with considerable shape
diversity without the need to produce multiple stereogenic centers with independent
control.4 Novel libraries were constructed from enantiopure cyclic hydrazine 1 by sequential
functionalization of each nitrogen atom using a range of C–N bond forming reactions
(Scheme 1). Crucially, the fluxional behavior of the pyramidal nitrogens within the resultant
sp3-rich heterocyclic framework 2 allowed it to adopt a well-defined conformation in which
2

each added fragment (R, R1 and R2) project away from its neighbors to minimize repulsive
interactions.4 Using this approach, chemical libraries displaying three-dimensionality and
shape diversity could be readily generated.
Scheme 1. New sp3-rich cyclic hydrazine frameworks for drug discovery.
In this earlier work, we focused on chemical libraries based upon larger hydrazine ring sizes
(n = 2-4). We also reported the synthesis of several derivatives of 1 (n = 1), but only
successfully converted it to 2 in the special case of R2 = H. In this article, we sought to
overcome this limitation by expanding the work to include the construction of libraries
based on 1,2-diazetidines (i.e. 2, n = 1). Importantly, we felt that the use of four-membered
ring scaffolds might offer several potential advantages. Firstly, due to their lower molecular
weight, a greater proportion of the members of the resultant chemical libraries would be
lead-like (MW <350), making them more useful in drug discovery.5 Secondly, derivatives
based on four-membered rings possess greater nitrogen pyramidalization due to ring strain,
offering distinct shapes in comparison to their larger homologs.6 Thus, a chemical library
including 1,2-diazetidines should benefit from increased shape diversity overall. Finally, for
this specific ring size, we anticipated new methods of synthesis would be available allowing
the introduction of a much broader range of fragments (R = H, alkyl and aryl) into starting
material 1 with defined stereocontrol.
2. Results and Discussion
Initial work focused on the synthesis of 1,2-diazetidines 5a-d from commercially available 2-
hydroxyethylhydrazine (3) bearing different protecting groups on the two nitrogen atoms
(Scheme 2).7 The synthesis began with conversion of 3 in two steps to 4a-d by selective
introduction of a carbamate group (Boc or Alloc) at the more nucleophilic nitrogen, followed
by sulfonylation (Ts, TIBS or dansyl) at the remaining nitrogen of the hydrazine.8 Final ring
closure to the 1,2-diazetidine was achieved in good yield either by Mitsunobu reaction (4a
and 4c) or via the corresponding iodide (4b and 4d). In the Mitsunobu process, either diethyl
azodicarboxylate (DEAD) or less hazardous diisopropyl azodicarboxylate (DIAD) can be used.
The two-step cyclization via the iodide was preferred in cases when the Mitsunobu by-
products proved difficult to remove by chromatography. For 4c, we were able to
unambiguously confirm its structure by single crystal x-ray diffraction (XRD).9
3

Scheme 2. Synthesis of differentially protected 1,2-diazetidines.a
a. Isolated yields correspond to the synthesis of 4 and 5, respectively
b. Boc2O, EtOH, RT, o/n
c. TsCl, pyr, THF, RT, o/n
d. DEAD or DIAD, PPh3, THF, RT, o/n
e. AllocCl, Et3N, CH2Cl2, RT, o/n
f. I2, PPh3, imidazole, THF, RT, 1 h; then Cs2CO3, MeCN, RT, o/n
g. TIBSCl, pyr, THF, RT, o/n
h. DansylCl, pyr, THF, RT, o/n
Next, we examined the synthesis of 1,2-diazetidines bearing a carbon substituent at C-3.
Several synthetic routes to enantiomerically enriched 3-substituted 1,2-diazetidines have
been described.4,10−14 Ma has reported the diastereoselective synthesis of 3,4-disubstituted
1,2-diazetidines via Pd-catalyzed cyclization of chiral 2,3-allenyl hydrazines with aryl halides
in good yields.10 Iacobini et al. made 3-methyl 1,2-diazetidines by Rh-catalyzed asymmetric
hydrogenation of 3-methylene-1,2-diazetidines.11a Rajkumar et al. have developed a route
to 3-vinyl derivatives via Pd-catalyzed asymmetric allylic amination of racemic vinyl
epoxide,14 and most recently, we reported an enantiocontrolled route to 3-aryl 1,2-
diazetidines using asymmetric transfer hydrogenation (ATH) as the key step 4
. Despite these
advances, no single method is suitable for the introduction of both aryl and alkyl
substituents, and a new more general route was sought for our needs.
To this end, we explored the controlled ring-opening of enantiomeric enriched epoxides
with hydrazine hydrate at the unsubstituted carbon atom.15 Enantiomeric enriched epoxides
6a-d were either commercially available or easily accessible by hydrolytic kinetic resolution
(HKR).16 After ring opening, the secondary nitrogen was selectively protected with a Boc
group to give 7a-d, which was further converted into 8a-d by tosylation of the primary
nitrogen and azodicarboxylate mediated Mitsunobu cyclisation (Scheme 3a).7 This epoxide
ring-opening strategy towards C-3 substituted 1,2-diazetidines was suitable for aryl as well
as alkyl substituents. Starting from enantiomeric enriched starting materials, C-3 substituted
diazetidines 8a-d were obtained in >95% ee as illustrated by the HPLC trace of enantiomeric
enriched 8b (Scheme 3b).7 The absolute stereochemistry of 8a was confirmed by
4

comparison with literature data,4 and the other examples assigned by analogy. In addition,
the method can be extended to annulated rac-8e using the same sequence starting from
meso-cyclohexane epoxide (6e).17 XRD structures of 8a and 8e clearly show an anti-
configuration of the nitrogen protecting groups with the latter structure displaying a boat
conformation of the annulated cyclohexane ring (Scheme 3, box insert).
Scheme 3. Stereocontrolled synthesis of 3-substituted 1,2-diazetidines.a
a)
1. H2NNH2•H2O
H2O (1 equiv)
EtOH, 0 °C to RT
2-18 h
1. p-TsCl, pyridine
THF, 0 °C to RT
18 h
Boc
Ts
R
OH NH2
NBoc
O
N
N
R
R
2. Boc2O, EtOH
0 °C to RT, 18 h
2. DEAD or DIAD
PPh3, THF, rt, 24 h
6a-e
7a-e
8a-e
Boc
Ts
Boc
Ts
Boc
Ts
Boc
Ts
N
N
N
N
N N
N
N
OPh
Ph
8
S-8a
R-8b
R-8d
R-8c
75%, 57%
59%, 49%
89%, 48%
75%, 76%
95% eeb
98% eeb
>98% eec
>98% eec
Boc
H
Ts
N
N
H
rac-8e
74%, 61%
8a, XRD
8e, XRD
b)
R-8b
S-8b
a. Isolated yields correspond to the synthesis of 7 and 8, respectively
b. Enantiomeric excess determined by chiral HPLC7
c. Enantiomeric excess determined after deprotection of the Boc group7
Next, we sought to build libraries from these differentially protected 1,2-diazetidines as
illustrated in Scheme 1. This necessitates being able to introduce a variety of substituents at
both nitrogen atoms in a controlled, iterative manner. To this end, we explored chemistries
suitable for the first functionalization step, by removal of either the sulfonyl or carbamate
N-protecting group. Starting from 5a, the Boc group could selectively be removed with
trifluoroacetic acid to give the mono-protected TFA salt 9 (Scheme 4, box insert);
neutralizing the acid with a sodium bicarbonate wash provided the free amine. Starting
from Alloc protected diazetidine 5b, treatment with Pd(PPh3)4 and phenylsilane provided
the same intermediate. This compound could be successfully functionalized by reductive
amination (10a), reaction with an isocyanate (10b), acylation (10c) or HATU-mediated
coupling to Fmoc-Ala-OH (10d) in good to excellent yields over the two steps.7 Alternatively,
the tosyl group from five representative 1,2-diazetidines (5a, 5b, 8b, 8c and 8e) was
selectively removed with magnesium in methanol and derivatized using an even wider
range of chemistries. Reductive amination (11a, 11b), acylation (11c-e, 11g), trapping with
phenyl isocyanate (11f), and Buchwald-Hartwig coupling (11h, 11i) were all successfully
applied to these substrates. Whilst Alloc-protected 5b could be used, the more modest
5

yields seen in the formation of 10d and 11d led us to conclude that Boc protection was a
superior choice.
Scheme 4. Selective deprotection/monofunctionalization of 1,2-diazetidines.a
R1
R1
1. TFA or
Pd(0)
’RO2C
Ts
’RO2C
Ts
1. Mg, MeOH
N
N
N
N
N
N
2. R1 addition
(see text)
2. R1 addition
(see text)
R
R
R
5a, 5b, 8b,
8c or 8e
11a-i
10a-d
R’ = tBu or allyl
Ph
Boc
H
Ts
N
Ph
Boc
N
N
N
N
N
H
10a: 65%b,c
11a: 92%d,c
11b: 76%d,c
O
O
Ts
PhHN
’RO2C
N
N
N
N
OMe
O
O
Boc
10b: 93%b,e
N
N
11c (R’ = tBu): 92%d,f
11d (R’ = allyl): 39%d,f
O
Ts
8
N
N
MeO
11e: 92%d,f
O
F
10c: 92%b,f
Boc
O
NHPh
N
N
Boc
H
O
N
N
H
FmocHN
Ts
11f: 60%d,e
N
N
Me
10d: 63%g,h
11g: 83%d,f
CF3
Boc
NC
N
N
Boc
N
N
11h: 40%d,i
OPh
11i: 31%d,i
9 TFA, XRD
a. Isolated yield over 2 steps
b. TFA, CH2Cl2, RT, 2h; then NaHCO3
c. RCHO, NaBH(OAc)3, THF, RT, o/n
d. Mg, MeOH, RT, 2h
e. PhNCO, CH2Cl2, RT, o/n
f. RCOCl, iPr2EtN, CH2Cl2, RT, o/n
g. Pd(PPh3)4, PhSiH3, CH2Cl2, RT, 2h
h. Fmoc-Ala-OH, HATU, iPr2EtN, CH2Cl2, RT, o/n
i. Pd(OAc)2, ArBr, Xantphos, NaOtBu, PhMe, 90 °C, o/n
Next, we explored the more demanding second functionalization step (Scheme 5).7 In this
case, both the steric and electronic demands of the substrates vary as a function of the
nature of the substituent introduced during the first functionalization. Despite this added
complexity, we were able to use all the chemistries described above to produce 12a-i in
yields ranging from 36-91% over the two-step process (average yield 65%). Indeed, the
approach works across a range of diazetidine frameworks including unsubstituted, 3-
substituted and annulated systems.
6

Scheme 5. Second functionalization of 1,2-diazetidines.a
a. Isolated yield over 2 steps
b. TFA, CH2Cl2, RT, 2h; then NaHCO3
c. RCHO, NaBH(OAc)3, THF, RT, o/n
d. RNCO, CH2Cl2, RT, o/n
e. Pd(OAc)2, ArBr, Xantphos, NaOtBu, PhMe, 90 °C, o/n
f. Mg, MeOH, RT, 2h
g. RCOCl, iPr2EtN, RT, o/n
It is possible to remove and functionalize the Boc and Ts nitrogens in any order. However,
generally we have observed better yields and fewer side products across a range of
substrates and chemistries when the Ts group is removed first. Reversing this order can lead
to unwanted side reactions, as illustrated in Scheme 6. Attempted Ts deprotection and
derivatization of 10c led to diamine 13 in low yield, instead of the expected 1,2-diazetidine
12b. This product presumably arises from reductive cleavage of the N–N bond during
treatment with magnesium in methanol to cleave the Ts group, with 13 produced after
trapping of the resultant primary amine with PhNCO. The structure of this compound was
established by NMR spectroscopy and confirmed by single-crystal XRD.7 Interestingly, more
forcing conditions such as Raney Ni and hydrogen are normally required to cleave the N–N
bond of 1,2-diazetidines,14 suggesting that this behavior is substrate dependent. The
electron rich aryl group and amide seem to make substrate 10c more prone for this
undesired pathway, no reductive cleavage was observed for diazetidine 10b under the same
reaction conditions.
7

Scheme 6. Unexpected ring cleavage reaction.
O
O
H
1. Mg, MeOH
2. PhNCO
26%
Ts
N
NHPh
N
H
N
N
MeO
O
MeO
10c
13
For three of the final products (12a, 12b and 12e) we were able to determine their solid-
state structures by X-ray crystallography (Figure 1). In each case, the N-substituents
displayed the expected anti-disposition and significant nitrogen pyramidalization
contributing to their three-dimensionality.18 In the case of 12b and 12e, an intramolecular
hydrogen bond was observed between the appended nitrogen fragments.
Figure 1. Representative XRD structures of difunctionalized 1,2-diazetidines with measured
values for the pyramidalization of the two ring nitrogens (N1 and N2).18
12a
N1 = 18.5°, N2 = 44.0°
12b
12e
N1 = 30.0°, N2 = 10.2°
N1 = 30.4°, N2 = 9.6°
3. Conclusions
New strategies for the synthesis of differentially protected 1,2-diazetidines have been
developed based on Mitsunobu ring closure of 2-hydroxyethylhydrazine derivatives. This
chemistry was successfully combined with the stereocontrolled ring opening of homochiral
1,2-epoxides by hydrazine monohydrate to realize the first practical synthesis of
differentially-protected, enantiomerically pure 1,2-diazetidines bearing either an alkyl or
aryl substituents at C-3. The methodology further provides access to annulated diazetidines
as illustrated by the synthesis of rac-8e from cyclohexane epoxide. A total of 9 differentially
protected 1,2-diazetidines were prepared through variation in the C-3 substituents and
nitrogen protecting groups. The chemistry is operationally simple and can be performed on
a preparative scale. Chemical library construction from these 1,2-diazetidines is possible by
iterative C–N bond formation at the two nitrogen atoms. Best results are achieved using
substrates bearing Boc and Ts groups using a sequence that involves initial removal of the Ts
group. Chemical diversification is possible through variation in the structure of the
heterocycle, use of different functionalization chemistries and coupling partners, and
controlled engagement of each nitrogen of the hydrazine in turn. X-ray crystallography
performed on three members of the final library reveal useful insights into how the
molecules sample chemical space. In all cases, the nitrogen substituents adopt the expected
8

anti-configurations and display significant sp3-character at nitrogen. Future work will
examine the feasibility of making larger chemical libraries based on these non-planar
scaffolds and the exploitation of them in drug discovery programs.
4. Experimental
All experimental procedures and characterization data for the new compounds, copies of
HPLC traces, 1H and 13C NMR spectra and XRD structures are provided in the Supplementary
data.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
We thank the Leverhulme Trust (RPG-2014-362), Eli Lilly and the University of Warwick for
generous financial support. Crystallographic data were collected using an instrument that
received funding from the European Research Council under the European Union's Horizon
2020 research and innovation program (grant agreement No. 637313).
Appendix A. Supplementary data
Supplementary data to this article can be found online at “add doi here”.
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11

Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: